Scientists have used gene therapy to make insulin-producing cells in a mouse’s pancreas
Insulin producing cells (like the ones shown in green) have
been made in a mouse’s pancreas. Photo credit by Masur.
A new study out in Nature shows how to turn one kind of pancreas cell into an insulin-producing islet cell. This research is an important step in finding a cure for Type 1 diabetes.

People get Type 1 diabetes when their bodies attack and destroy their own islet cells. These people can’t make insulin anymore and so have to inject it. The best cure would be if scientists could replace the old islet cells with new ones. This is what the researchers in this study set out to do in mice.

The researchers made islet cells directly in a mouse’s pancreas. They did this by using gene therapy to reprogram one type of pancreas cell (an exocrine cell) into islet cells.

All cells share the same DNA. What makes each cell type different is which genes are on (or have been on in the past). Proteins called transcription factors are a big part of this programming.

The authors reasoned that they might be able to directly reprogram one kind of adult cell into another by adding the right mix of transcription factors. They couldn’t just add transcription factors though. Instead, they added transcription factor genes*.

Finding the right transcription factors was not simple. There are thousands of these things scattered throughout our DNA.

The researchers narrowed the list of possible candidates down by looking at those that were found in the pancreas. And then they further narrowed down the candidates by mutating these transcription factor genes and looking for effects on pancreas development. Nine transcription factors made it through these tests.

By testing different combinations of these genes, the authors were able to find a cocktail of three that turned an exocrine cell into an islet cell. These new cells looked and acted like islet cells. And what is also important, the new cells stayed islet cells even after the transcription factors were gone.

One of the big problems with gene therapy is that eventually the body recognizes the viral DNA as other and shuts it down. So the best gene therapies are the ones like this–the hit and run kind.

This is all very promising but the procedure is nowhere near ready for prime time yet. One problem, of course, is that mice aren’t people. What worked in a mouse might not work in a person.

An even bigger problem is that the created islet cells are scattered here and there throughout the pancreas. Islet cells work best in clumps (as they exist naturally). So scientists will need to figure out how to get them to clump together.

* Transcription factors are proteins and like all proteins, their instructions are found in genes.

Last blog I talked about how scientists turned skin cells into embryonic stem (ES) cells. This was big news because scientists can now make an ES-like cell without destroying an embryo.

This blog I thought I’d talk about how scientists have used these cells to cure a mouse’s sickle cell anemia. If the mouse stays cured, this is a hugely important finding.

First some terminology so I don’t have to keep saying, “skin cell turned ES cell.” Scientists are now starting to call these cells iPS for induced pluripotent stem cells and I figured I’d jump on the bandwagon too. (Pluripotent is just a way to say that a cell can turn into lots of other kinds of cells).

Now as you probably know, sickle cell anemia is a genetic disease that is more common in people whose ancestors came from areas where there was lots of malaria. In sickle cell anemia, the red blood cells “sickle up,” forming crescent shapes. These shapes can’t fit in the smallest blood vessels causing the problems associated with the disease. Right now there are treatments but no cure.

The way to cure the disease is to fix the broken hemoglobin gene in the cells that make red blood cells. Since red blood cells are all replaced within a few months, this would lead to a cure pretty quickly.

Unfortunately, fixing a gene is not like falling off a log–it is really hard to do. The scientists in this study decided to try it with iPS cells. Basically they replaced the mouse’s blood stem cells with newly repaired ones so that the new blood stem cells made healthy new red blood cells. The mouse has not shown signs of sickle cell anemia for 12 weeks so far.

I don’t want you to come away thinking that it was an easy thing to do. It wasn’t (see below). But it does show that it is possible to treat and possibly cure sickle cell anemia in mice using iPS cells.

To move it to humans, we need to make sure that the treatment sticks. When these kinds of things have been tried with gene therapy, the cure almost always wears off over time. It shouldn’t happen at the DNA level with the way they did their experiment, but we need to wait and see.

The scientists also need to find genes that can turn a skin cell into an iPS with less risk of causing cancer. And to find better ways to get these genes into the skin cell so that, again, the treatment doesn’t cause cancer.

Even taking all of this into account, this is a very promising first step. Curing a genetic disease with stem cells that do not get rejected by the recipient’s body is one of the big goals of stem cell research. And these researchers may have accomplished this in mice.

More details on how to cure a mouse’s sickle cell anemia:

1. Add four genes to turn the skin cell into an iPS cell.

See the previous blogto see how to do this. To decrease the risk of the mouse developing cancer from these cells, the researchers chopped out one of the genes they used, the myc gene.

2. Use the ES cell to fix the gene using a process called homologous recombination.

Homologous recombination is a way to swap out one DNA for another. It is incredibly inefficient and we can really only get it to work at all in ES cells. Out of 72 cells, they managed to get one where one copy of the gene was repaired.* This result showed that homologous recombination would work in iPS cells which was an open question.

3. Turn the ES cell into a blood-like stem cell by adding the HoxB4 gene.

4.Destroy the mouse’s bone marrow and replace the cells with the new blood stem cells.

This is really just a bone marrow transplant using the newly created cells as the blood stem cells.

*In the end they had a mouse with one of its copies of the hemoglobin gene repaired in its blood cells. (All the rest of the cells including its sperm cells still carried the disease version of the hemoglobin gene.) The mouse exhibited no sickle cell anemia symptoms similar to most human carriers of the disease who have a single broken copy.

Dr. Barry Starr is a Geneticist-in-Residence at The Tech Museum of Innovation in San Jose, CA.

latitude 37.3316, longitude -121.89

Scientists can now turn skin cells into embryonic
stem cells like these.(Image: Nissim Benvenisty)It is amazing how fast stem cell research is accelerating. Six months ago, we had to destroy embryos to get at their precious embryonic stem (ES) cells. Or we had to at least steal them.

Now, as 2008 begins, we can turn skin cells into ES cells in mice and humans. This is huge and here’s why:

1) No embryos need to be destroyed
2) No one needs to be cloned
3) ES cells derived from skin cells won’t be rejected by the body

So how’d the researchers do it? As with any important new finding, this one started out as basic research. And like many other findings, this one also started out not in humans but in an animal model system.

A Japanese group had been studying how a mouse ES cell eventually gets turned into a skin cell. In the end, they identified around 20 genes that were turned on to reprogram a skin cell into an ES cell.

The 20 genes the Japanese group identified are really master control genes. They are responsible for affecting how lots of other genes work. So, all a scientist would have to do is turn on these 20 genes in a skin cell and you’d get back to an ES cell. Sounds simple, right?

Unfortunately, scientists aren’t very good at all at turning on a specific gene in a cell let alone 20. To get around this limitation, the scientists decided to add the genes to a skin cell using gene therapy.

Unfortunately, scientists can’t easily add 20 genes to a cell with gene therapy either. This meant they had to find the bare minimum that might work. After much research, the group settled on four genes that could turn a skin cell into an ES cell.

Remember, this was all in mice. Now this same group (and another from the U.S.) has accomplished the same thing with a human cell. Both groups have taken a human skin cell, added four genes, and changed it into an ES cell.

We aren’t going to be curing diseases with these cells quite yet though. When the Japanese group put the mouse cells back into a mouse, 20% of them developed cancer. This is probably due to one of the genes they used (myc), as well as the way they did their gene therapy (viral mediated).

The U.S. researchers who converted the human skin cell were able to do it without the myc gene. This tells us there are different sets of genes that can work in this process. Hopefully scientists can discover a set of genes and a way to get them into cells that won’t cause cancer.

All this work got me to thinking. I wonder if scientists would have worked this hard to make ES cells from skin cells without George Bush’s ban on ES cell research. They certainly would have got there eventually but would they have gotten there so quickly?

Dr. Barry Starr is a Geneticist-in-Residence at The Tech Museum of Innovation in San Jose, CA.

latitude 37.3316, longitude -121.89