AN update: disease in a dish

Which psychiatric disorder has the highest mortality rate?  

If you are an avid NeuWrite reader, you might remember from a past article that the answer is anorexia nervosa (AN).  Some sources report a mortality rate as high as 20%, with death often as a result of heart failure, malnutrition, or suicide [1].  While there is a clear genetic component to anorexia [2], large genetic studies have so far been unable to pinpoint specific genes that underlie the disorder.  However, a new approach to finding the culprit genes may eventually lead to more promising treatment options.

Diseases in a dish

While the phrase “stem cells” used to spark bitter controversy, scientists can now take a harmless skin biopsy from a human patient and transform those (skin) cells into stem cells capable of becoming many different types of cells in the body, including brain cells.  They are aptly named “induced pluripotent stem cells” (iPSCs).  Using this technique—and without going anywhere near a patient’s brain–scientists are able to create a dish of brain cells with a patient’s exact genome.  They can then determine whether the genetic makeup of these cells makes them unusual in any way compared to cells from healthy individuals.  These “diseases in a dish” may prove exceptionally useful for testing potential drugs, as discussed in a previous post about Alzheimer’s disease.  Instead of giving possibly harmful or useless drugs to the patients themselves, scientists can apply some of the drug to the same patient’s iPSCs to see if it helps counteract whatever is wrong.

culture hood

Recently, a group of scientists led by Alysson Muotri based here in San Diego created an iPSC model of anorexia—they took skin cells from 4 patients with anorexia and 4 healthy individuals, reverted them to stem cells, and then turned the stem cells into brain cells.  They found 248 protein-coding genes (genes that contain the recipe for a certain protein manufactured in the cell) that showed either increased or decreased expression in cells from patients with anorexia compared to those from healthy individuals [3].  Among the genes were some involved in energy storage, ovulation, and chronic stress. [4-6].  Both energy storage and ovulation are disrupted in AN, and chronic stress is thought to contribute to disease onset.  It seemed as if the results were leading down a promising path.

Digging through the data

It’s difficult to know where to start when you have a list of 248 genes, so the researchers used online databases to find out more about the proteins that those genes code for.  More specifically, they looked for other proteins that those 248 proteins are known to interact with and signaling pathways that they are known to be a part of.  The scientists expected to find differences between patients with anorexia and healthy controls in the levels of neurotransmitters (signaling molecules) used in the brain’s food intake, reward, and mood signaling systems—serotonin and dopamine.  They didn’t.  As is often the case in science, they found something interesting that they had not been searching for.  

Based on their database search, they turned their attention away from the classic neurotransmitters to the tachykinin signaling pathway.  The gene for tachykinin 1 receptor (TACR1) was among those 248 genes changed in AN, and others on the list were also associated with the same pathway.  Interestingly, this pathway has been linked to addictive behavior, bipolar disorder, depression, anxiety, hyperactivity, body mass index (BMI), and the reward pathway in rodent studies [7-13] but had never before been specifically connected with anorexia.  And TACR1 expression in healthy individuals peaks in adolescence in the striatum—a time and brain region particularly relevant to anorexia.  Most of those with anorexia develop the disorder during adolescence, and the striatum is the center of the brain’s reward system, a system disrupted in addictive behaviors.

Going forward

The results of this study are exciting, providing not only a clue as to what is going wrong in the brain during anorexia but also providing a potentially revolutionary method of modeling the disorder (iPSCs!).  Of course, this comes with a very specific grain of salt: the sample size was extremely small (8 people total, 4 per group).  The findings will need to be confirmed within a larger group of people.  The study, however, provides hope that drugs targeting the tachykinin system will someday prove to be useful in treating anorexia nervosa and decreasing the shocking number of associated deaths.


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