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 cells model heart disease, test drugs

Nature has a story that features a promising use for stem cells, and also provided a creative outlet for whoever is writing headlines over there: “Cells snag top modelling job”.

Nature isn’t covering America’s top model. They’re talking about modeling disease, in this case a heart condition called long QT syndrome. Both embryonic or iPS cells can be matured into any adult cell type. If those cells carry mutations that cause disease then they’ll mature into adult cell types that, in some cases, display that disease.

For something like long QT syndrome, in which the heart tissue has an altered beat, stem cells carrying a mutation that causes the condition provide the only way of testing drugs in a lab. The story mentions Mike Venuti, president of CIRM-funded biotech company iPerian:

His firm has made iPS cells from people with Alzheimer's disease, Parkinson's disease and type 2 diabetes and converted them into various cell types for drug screening. He expects that drugs identified using this method will reach clinical trial for conditions such as spinal muscular atrophy in the next few years.

CIRM funds work by Bruce Conklin at the Gladsone Institute of Cardiovascular Disease, who is taking cells from people with heart conditions, creating iPS cells, and using those cells to study the condition and test drugs. This video features Conklin discussing his cells’ top modeling work.



- A.A.

Top four list: why embryonic stem cells are critical

Yesterday CIRM grantee Bruce Conklin gave his top four reasons why embryonic stem cells are so valuable and why federal funding for the work needs to be able to continue. Conklin, who is Senior Investigator Gladstone Institute of Cardiovascular Disease and professor at UCSF, studies heart rhythm defects by creating iPS cells from people genetically predisposed to have those defects, then maturing those into heart cells in a dish. This gives him a way of studying the rhythm defect in the lab, and allows him to test drugs that might correct the arrhythmia. (You can see his New Cell Lines Award research summary here.)

Conklin says he’d never be able to carry out his iPS work without advances made with embryonic stem cells. Here’s his list:

1) Scientists have genetically engineered embryonic stem cells that are widely used for studying specific processes in the lab. “Obviously, we can remake those cells lines using iPS cells but it’s a huge waste of time,” he said. Instead of making progress toward developing new therapies or finding new drugs, labs would have to spend years redoing work they’ve already done.

2) Embryonic stem cells are farther along clinically than iPS cells or the new directly reprogrammed cells. “The first clinical trials of pluripotent cells will be embryonic stem cells. Ten years from now we’ll probably see a mix of embryonic and iPS cells,” he predicted. Adult cells are good for many things, he said, but aren’t as flexible as pluripotent embryonic or iPS cells.

3) Embryonic stem cells reproduce the steps taken by nature. “The idea is that nature knows something we don’t, because we don’t know very much,” Conklin said. Studying embryonic stem cells as they go down the path toward a specific cell type, like a skin cell or a neuron or a pancreatic islet cell, can give us clues about what might be going wrong in diseases afflicting those cell types.

4) Some diseases seem to begin at the earliest stages of development. “If we are going to understand human development we have to know how the process happens naturally,” he said. Only by studying embryonic stem cells can we understand genetic diseases that strike at the earliest stage, or what’s called epigenetic changes that can alter the way genes function.

Conklin seemed optimistic about the future of iPS and direct reprogramming, but pointed out that even Jamie Thomson, who was part of one of the two teams that first created iPS cells, has predicted that iPS cell research would be five years ahead of where it is now if embryonic stem cell research weren’t slowed under the Bush funding regulations.

The CIRM Governing Board recently passed a resolution that “strongly encourages federal policy that supports all forms of stem cell research for the millions of Americans who suffer from disease and injury and strongly supports criminalizing human reproductive cloning.” You can read Resolution 2010-01 here, which supports both the DeGette and Spector legislation “or any successor legislation that embodies the policies advanced in President Obama’s Executive Order 13505 and the National Institutes of Health July 7, 2009 guidelines on hESC research.”

A.A.