Genetic disease may be as different as different kaleidoscope pictures. This complicates finding the cause of most genetic disease.

Scientists have thought that they had a pretty good handle on how genetic diseases work. A certain DNA difference causes a certain gene to work incorrectly leading to a specific genetic disease. And importantly, people with a disease tend to share the same DNA difference.

A disease like sickle cell anemia (SCA) is a perfect example. A key DNA difference in the hemoglobin gene causes sickle cell anemia and many people with SCA have the exact same difference.

But what if diseases like SCA are the outliers? What if instead most people or families had unique DNA differences that led to their disease? Then scientists have been going about finding the causes of genetic disease in the wrong way.

Right now scientists tend to do something called genome wide association studies (GWAS) to find the causes of genetic diseases. Basically scientists compare the DNA of people with a disease to people without the disease. If they compare enough people, they should be able to pinpoint the differences that matter.

This strategy is based on people with the same disease having the same DNA differences. If people have unique differences, then this strategy won’t work. And so far, most GWAS studies have not found a lot.

They have tended to find a few DNA differences that can explain a very small part of any disease when they look at related groups like Icelanders or Northern Europeans. And even these small effects sometimes go away when scientists try to apply them to larger, more diverse groups.

This is just what you might expect with unique, recent DNA changes causing disease. And if you stop and think about it, the idea of lots of unique DNA changes leading to common diseases makes some sense.

Each person in each generation has around 175 new DNA changes that their parents didn’t have. Spread out over the human race over hundreds or thousands of years, that is a lot of relatively recent differences.

Any DNA change that has too severe an effect on a person shouldn’t survive long in human DNA. People with the change will be at a disadvantage and so won’t do as well as people without the change. Over time, the change will disappear.

The exception to this is if the change can have both good and bad effects. SCA is obviously bad but in areas with a lot of malaria, it is actually helpful. People who carry SCA but do not have the disease are more resistant to malaria and do better. Most bad DNA changes won’t come with benefits though.

So instead of a set of static DNA differences that are passed down we might need to think about human DNA as constantly changing. Many DNA differences come and go over time. In this scenario, most human disease is caused by DNA changes in the process of being eliminated. Or they are neutral changes that have turned bad now that we live in a new environment. (Think having lots of food, living longer, having fewer babies, etc.)

If this is how things work, then GWAS won’t find much. And as I said before, they really haven’t. But luckily there are other ways to skin a genome.

Even if people have unique DNA changes that lead to disease, there will be overlap in the affected genes. One approach is to look at the DNA of people with severe forms of a disease to find the gene involved.

Then you’d have to sequence the whole gene and look for changes. The sequencing will be easy…we can sequence a gene in no time these days. The hard part will be figuring out which changes matter. There are bound to be lots of differences in most genes with hardly any of them having any effect. So scientists will need to come up with some way to tell which changes matter.

If this is how genetic disease works, more traditional sorts of DNA tests are in real trouble. And we’ve spent an awful lot of time and money heading down blind alleys. But that’s how science works, two steps forward, one step back.

A couple of in-depth looks at this problem:

Genetic Heterogeneity in Human Disease

Beyond genome-wide association studies

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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.

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