Stem Cells

I heard recently that they created stem cells from other somatic cells of the body. How is this possible?

-A curious adult from California

October 2, 2008

Scientists have done some amazing things lately with stem cells. And one of the most amazing is creating embryonic stem (ES) cells* from other kinds of cells.

Scientists first managed to turn a human skin cell into an ES cell in 2007. They did it by reprogramming the skin cell's DNA.

To understand what this means, we first need to understand how different types of cells come about. Then we can see how to reprogram one cell type into another.

Genes Determine Cell Type

Almost all cells share the exact same DNA. That DNA has all the instructions for making and running every kind of cell in the body. In other words, the DNA in each of our cells has the potential to create any other kind of cell.

So why are some cells skin and others nerve? It has to do with which genes are turned on in any given cell.

Genes are really just instructions for making proteins. And proteins do all the work in a cell. Each protein has a very specific task.

For example, hemoglobin carries oxygen to and carbon dioxide away from our cells. Like every other protein, the instructions for hemoglobin are found in a gene that is found in nearly every cell. (Well, hemoglobin actually needs more than one gene.)

Hemoglobin is absolutely critical for letting our blood carry oxygen to our cells. But making it in a nerve cell wouldn't be helpful at all. Nor would it help to make hemoglobin in a fat or skin cell either.

We have evolved a system that keeps the hemoglobin genes on in the right cells. And shuts them off in the wrong cells.

This system also controls which of our over 21,000 genes are on or off in all of our different cell types. So a skin cell is a skin cell because of the genes that are on and off in the cell. And a nerve cell is a nerve cell because a different set of genes are on or off there.

So to make an ES cell from, for example, a skin cell, we only need to turn on the ES genes and turn off the skin genes. And this is just what scientists have done.

How to Program a Cell

As I said, a skin cell has a whole different set of genes that are turned on compared to a nerve cell. Or to an ES cell.

It would be very hard to have to go in and tweak each gene individually. Luckily we don't have to. Our cells make proteins called transcription factors that can tweak many different genes at once. It is these proteins that set up a cell's programming.

We all start out as ES cells. Each ES cell then turns on a different set of transcription factors to turn into a different kind of stem cell (called a somatic or adult stem cell). For example, the ES cell can become a blood stem cell. Or a skin stem cell. Or one of many other kinds of stem cells.

These adult stem cells go on to form all of the different kinds of tissues that make up a person. They are also responsible for replacing our worn out cells. As cells die off, adult stem cells make replacements.

They do this by, you guessed it, turning on different transcription factors. For example, a blood stem cell can turn on one set of transcription factors to become a platelet. And a different set to become a red blood cell.

To turn cells back into ES cells, scientists needed to find the right combination of transcription factors to reprogram a cell back into an ES cell. And they needed to add the genes for these transcription factors back to the cells.

How to Reprogram a Cell

There are over two thousand transcription factor genes in a cell so finding the right ones was no easy task! But they did it. Researchers compared a skin cell to an ES cell and found many transcription factor differences. (Luckily there weren't 2000 of them!)

The next step was to add the transcription factors they discovered back in various combinations to a skin cell to see which set would turn the cell into an ES cell. The researchers did this with gene therapy.

Basically the researchers added each of the transcription factor genes they found into the DNA of a virus. This virus had its dangerous genes removed but it could still infect a cell. And add its DNA to the cell's DNA.

After a lot of trial and error, the researchers found it took four genes, OCT3/4, SOX2, KLF4, and c-MYC, to turn a skin cell into an ES cell. These four transcription factors were able to reprogram the skin cell's DNA so that the skin cell became an ES cell.

This combination had problems though. Not only was the whole process very inefficient, but around 20% of the time the reprogrammed cell turned cancerous! Most of the work done lately has been trying to make the whole process more efficient. And less dangerous.

One of the most exciting improvements has been to start out with an adult stem cell instead of a skin cell. Researchers reasoned that since an adult stem cell is more closely related to an ES cell, it might take fewer genes to turn one into an ES cell. And they were right. It only took two and neither caused the cells to become cancerous.

The Future

The next step will probably be to find chemicals that can mimic the effect of adding these two genes. If researchers can do this (and they have started to look into it), then creating ES cells should be easier than ever.

There you have it. Making ES cells requires adding a few genes back to a cell. This reprograms the cell back to its original ES state.

Now researchers can get to work using these cells to cure incurable diseases and fix unfixable injuries. They'll do this by changing the ES cells into cells that our bodies can't naturally replace. Or by fixing the cell and putting it back into the patient.

This means that one day scientists may be able to use ES cells to repair severed spines so the paralyzed can walk again. Or ES cells can one day be turned into islet cells to cure people of diabetes. Or they may even be used to cure sickle cell anemia.

The next step will be to figure out how to safely turn these ES cells into the cells the patient needs. I can't wait to see the next results!

*Created ES cells are called iPS cells. iPS stands for induced pluripotent stem cells.

By Dr. Barry Starr, Stanford University

ES cells can become any other kind of cell.

Scientists used gene therapy to turn a skin cell into an ES cell.