CLEVELAND, Ohio– Imagine cooking up a new recipe for carrot cake and trying to figure out what it tastes like by feeding it to your dog. You might be able to learn something from his reactions — Does he eat some? A lot? Does he, heaven forbid, keel over afterward? — but you’d be pretty limited by some basic differences between you and your canine friend. Even if he could somehow tell you what he thinks, there’s just no telling if cake tastes the same to a dog.
This is something like the problem faced by researchers who are trying to understand and treat devastating human brain diseases like Parkinson’s and Huntington’s by working with mice.
The mouse brain has told us a lot about the diseases, but, in the end, it’s only a stand-in for working with the real thing.
Now the real thing is here. Two groups of Parkinson’s and Huntington’s researchers working in 13 labs nationwide have used advanced stem-cell technology to make human brain cells from skin cells donated by patients with those diseases. The brain cells look and act like cells affected by the diseases, and they can be manipulated in a petri dish.
Working with the new cells in a petri dish is a little like taking a bite of your recipe and getting your own reaction, without the potential of making yourself sick.
It’s a first for the field, says Dr. Christopher Ross, one of the Huntington’s disease study’s lead researchers and professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine in Baltimore.
“It’s going to be a tremendous opportunity to study the disease, to understand it, and particularly to develop therapeutics,” he says.
Huntington’s disease is inherited and caused by a defect in a single gene. The disease is progressive and fatal, causing twitching and jerking movement, dementia and brain-cell death. It affects about 30,000 people in the United States. Parkinson’s, while not fatal, affects about 1 million Americans and causes progressively worsening movement problems as well as mood and sleep disruptions.
The technology that made the recent advance possible, called induced pluripotent stem cells, or iPSCs, was developed about four years ago simultaneously at the University of Wisconsin and in Japan.
In short, iPSCs are adult cells (usually skin or blood cells) taken from a donor with the disease and then genetically reprogrammed, or induced, back to their most primitive state. Once they are turned into stem cells, they can be forced to develop into any cell in the human body.
In the case of Huntington’s disease, researchers forced the skin cells of donors into medium spiny neurons, the type of brain cell that is targeted by the gene defect that causes the disease. For Parkinson’s, scientists created dopamine neurons. Parkinson’s occurs when these brain cells are slowly destroyed.
“Until this technology came along, we never expected to be able to have a model with human cells that we could test in culture,” Ross says. “I’m a psychiatrist and a neurobiologist, and I’ve been studying [Huntington’s] for many years. But I never would have imagined that I’d have stem cells that I could make into neurons and study them in culture.”
The iPSC technique means that the groups didn’t have to use embryonic stem cells to perform their research, avoiding the associated controversy.
In the case of one of the Huntington’s patients, Ross says, the donor was a 7-year-old girl with a particularly aggressive form of the disease, which usually manifests when a person is in her 20s or 30s.
“One of the things that I was very impressed by was the child being willing to have the biopsy done, and her mother being very enthusiastic even though she knew her daughter wasn’t going to get any direct benefit from the study,” he says. The child has since died, Ross says. “She wanted to contribute to the research.”
It took about two years to develop the brain cells they needed from the donated skin samples using the iPSC technique, Ross says.
Ross’ group, the Huntington’s Disease iPSC Consortium, published its research online this month in the journal Cell Stem Cell. The group includes researchers from the University of Wisconsin School of Medicine; Massachusetts General Hospital and Harvard Medical School; the University of California, San Francisco; Cardiff University in Wales; the Universita degli Studi di Milano in Milan, Italy; and the CHDI Foundation Inc.
Having cells that look and act like human Huntington’s neurons means that researchers can confidently test new drugs to treat and prevent the disease, Ross says.
“In preliminary studies, our lab and a couple of the other labs in the consortium have found molecules that can actually block the cell death [involved with Huntington’s],” he says.
“Despite all the scientific advances, we don’t have any effective therapeutics that can delay the progression or delay or prevent the onset of these diseases. We think this is going to be the means to develop that kind of therapeutic.”