In the past decade, great strides have been made in the field of stem cell technology, including the tantalizing idea that we may one day be able to replace brain cells ravaged by diseases such as Parkinson’s and Alzheimer’s. Researchers have learned to reprogram fibroblasts, a specialized type of human skin cell, and turn them into brain cells in the lab, offering new models for studying the disease progression and potential tools for personalizing therapies for each patient. Now, researchers at Sweden’s Lund University have reported a new technique that reprograms stem cells into neurons directly in the brain.
Working in vivo
Malin Parmar, a neurobiologist at Lund University, has been working towards the ideal of cell replacement therapy for some time. Many replacement techniques have been thwarted by problems like cell rejection or tumor development. She and her colleagues wondered if they might be able to avoid these obstacles by using the brain itself as the petri dish.
The group designed reprogramming genes that could be activated or deactivated using the drug doxycycline. They inserted these genes into fibroblasts in the laboratory and then injected these doctored cells into living rats. Then they put the activating drug through in the animals’ drinking water.
“As the rats drank the water with the doxycycline in it, it activated the genes and reprogrammed the fibroblasts into neurons within the brain,” says Parmar.
In a second study using mice, the researchers were able to repeat the process—this time using the animal’s own glial cells, the white matter brain cells that provide support and nourishment to neurons. Parmar argues that this type of technique may prove a better basis for human cell replacement therapies.
“Taking a long-term perspective, if you can obtain cells with the same quality and at the same frequency, there are advantages to doing the reprogramming directly in the brain,” she says. “You don’t need to collect and culture cells. You can skip the in vitro step. When it comes to dealing with regulatory and safety issues, I think the simpler you can do it, the better.”
Replacing dopaminergic cells
Parkinson’s disease is characterized by the profound loss of dopaminergic neurons in an area of the brain called the substantia nigra. Perhaps someday, stem cell therapies could replace these vital cells.
“In this study, we’ve shown that one can generate neurons by direct conversion in vivo. We can now use this technique to generate dopaminergic neurons,” Parmar says. “Once we succeed in generating a high number of these cells, we will then test whether these neurons can function in the brain and whether they restore the motor and other symptoms you see in animal models of Parkinson’s disease.”
She argues that previous clinical trials have demonstrated that transplanted fetal cells can work, but there simply weren’t enough cells available to turn the tide of disease progression. “If we can use somatic cells and then directly convert them in the brain, we may be able to reverse the loss of dopaminergic cells in the substantia nigra,” she says.
But Lawrence Goldstein, a pioneering researcher in the stem cell field, points out that successful cell replacement therapies have to do more than just replace to be successful—they have to connect and integrate into existing brain circuitry.
“One still has to worry about the wiring, how everything is working together,” he says. “If you’re trying to treat a patient in advanced stages of neural degeneration, it’s hard to know what’s involved in trying to not only generate large numbers of neurons in the brain but also make sure they re-connect in the right way. It may not be straightforward, especially if you are talking about treating a 70-year-old patient.”
Still, he says this technique may hold some promise in diseases with more focal neurodegeneration, like Parkinson’s. “If you are just trying to target the striatum, it may be a more straightforward process,” he says. “But in diseases like Alzheimer’s, you see degeneration in the hippocampus and the frontal lobes. There’s a much larger volume of cells and circuitry that would need to be replaced. Even using direct reprogramming of cells in the brain, you run into the same problems that more traditional replacement techniques been running into for years: How do you generate enough of the right cells? How do you deliver enough of whatever factor to enough of the right cells at the right time to fix the problem? It’s really complicated.”
Parmar agrees that there is still a lot of work that needs to be done before cell replacement could be a viable treatment.
“Within five years, we are likely to see the results of the first human embryonic stem cell trials. By then, we’ll have a whole set of alternative cells that will have been developed and ready to be tested,” she says. “Before we can think about transplantation as a therapy, we need to establish the functionality of this kind of technique in animal models of Parkinson’s disease and then move to clinical trials. You also need to prove that it is safe. With any type of stem cell therapy, safety remains a big concern.”
But Su-Chun Zhang, a neurobiologist at the University of Wisconsin-Madison who also studies transplantation techniques, cautions that we may need to slow down. The next few years should be dedicated to modeling and discovery work so we can better understand the intricacies of cell replacement, Zhang says.
“There are many interesting techniques out there now. Many of them can develop fairly clean cell systems, and potentially safe cell systems that may one day work for transplantation,” says Zhang. “But we are not there yet.”