Embryonic stem cells from skin cells

How scientists used gene therapy to make embryonic stem cells

Japanese scientists have turned skin cells into embryonic stem (ES) cells in mice using gene therapy. If scientists get this to work in people, all of the ethical problems associated with ES cells will melt away.

Of course there are a lot of technical hurdles to get this to work in people. For example, when scientists used these ES cells in mice, 20% of the mice died of cancer. But the risks and hurdles are worth overcoming because ES cells have so much potential.

ES cells hold the promise to treat previously incurable conditions like spinal cord injuries and diabetes by growing new tissues. But using these cells is controversial. Why?

First off, an embryo usually has to be destroyed to get its stem cells. To people who view these few cells as a life, this is not acceptable.

Another concern revolves around the fact that the most useful ES cell will be one that has the patient's DNA. These "personalized" ES cells won't suffer from the rejection problems doctors see with organ transplants because any tissue grown will have the same DNA. The patient's body is happy to welcome home the new heart or kidney or whatever as long as it has the patient's DNA.

Right now the only way to get ES cells from an adult is to clone that adult. Besides having to destroy this embryo, this procedure also opens up the possibility for growing a full clone of the adult. No reputable scientist would do this but the risk is there.

Besides these ethical problems, there are other practical problems in cloning an adult. You need to get a lot of unfertilized human eggs to make a clone and these are hard to get. We also haven't yet cloned a person. Of course this will eventually be overcome but we don't know when.

This new research gets around many of these problems. By adding just 4 genes to a skin cell, these scientists turned a skin cell into an ES cell.

Just think, ethical stem cells from the patient. This will open up all sorts of possibilities in personalized medicine.

What makes an embryonic stem cell so special anyway?

Embryonic stem cells are different from other cells in a couple of ways. The first is that they have not yet decided what kind of cell they will become. They are blank slates.

This means they have the potential to become any other kind of cells. Most other kinds of cells are stuck being what they are. A skin cell pretty much stays a skin cell (unless it becomes cancerous).

The other property that makes ES cells so special is that they can keep making copies of themselves. Most other cells can't do this. Once a skin cell is a skin cell, it doesn't make new copies of itself. When its useful work is done, it dies and is replaced.

So what's the difference between an ES cell and a skin cell? Why can an ES cell do all of these things but not a skin cell? Mostly it has to do with what genes are turned on and what the DNA looks like. (These two are actually connected.)

Remember, in order for its effects to be felt, a gene has to be on. And different cell types have different genes turned on and off.

This makes sense if you think about it. A skin cell has different needs than a liver cell. The skin cell needs to protect us from the outside world. And a liver cell needs to, among other things, protect us from poisons by breaking them down.

Why would you have liver genes on in skin? It is a waste of energy. So these genes are not on in the skin.

The pattern of what genes are on and off is set up when a stem cell becomes a final cell type. The pattern is set up by proteins that can change the DNA so that cells no longer recognize a gene. Or these proteins can point the gene out to the cell.

As you may recall, proteins come from genes. So the proteins that set up these patterns are because of specific genes.

Now, when an egg is fertilized, these patterns need to be erased. The DNA needs to be made into a clean slate again.

Proteins do this work too. Which means there are genes whose job it is to erase the patterns in our DNA. These are the genes scientists added to a skin cell to turn it into an ES cell.

More Information

Embryonic stem cells
can become any
other kind of cell.

How to make a skin cell into an ES cell

OK, so now we know the problem. There are certain genes needed to make a cell turn into an ES cell. Since these genes are presumably off in a skin cell, we need to turn them on again. And have all of the skin cell genes shut off too.

The way the scientists decided to do this was to add back whatever genes are needed to erase the pattern in the skin cell. (These genes are off in a skin cell.) This is a lot easier than specifically turning on this small set of genes.

The way they decided to add back the genes was with a virus. A lot of gene therapy gets done this way.

Many viruses work by sticking themselves into a cell's DNA. What the scientists planned to do was to take out some of the nonessential virus DNA and put in the necessary genes.

We're all set except we don't yet have the genes. Scientists had figured out through various means that if they added 24 different genes to a skin cell, it would turn into an ES cell. Yikes!

That is way too many to do gene therapy. So they started taking one away at a time to find the really key ones. They finally settled on 4 genes. This is still an awful lot but it is at least doable.

Last year they added back these genes and got some promising results. The skin cells took on many of the properties of ES cells but not all of them. This is encouraging but not good enough.

To fix this, they changed the skin cells to make selecting the most ES-like ones easier to do. When they did this, they were able to grow cells that essentially looked like an ES cell.

As a final test, they added some of these cells to an early mouse embryo. The embryo grew into a pup that contained different cell types derived from the original embryo and the skin cells (a chimera). This test proved these cells had been turned into something that could be used as ES cells.

Cool. But it is not a slam dunk to get this to work in people. We don't know if these same 4 genes are the ones that work in people too. And around 20% of the mice died from cancers caused by one of the added genes.

But these are problems we can deal with. Of course we'll have to continue to use "real" ES cells to figure out the genes needed to turn skin cells into ES cells. In other words, we need to destroy embryos now to stop destroying them in the future.

This research will progress very quickly. Because the experiments are easier to do than cloning, little labs all over the world can tackle these kinds of questions with no government interference. Personalized medicine may be here sooner than we think.

Four genes, possible
new lease on life.