Redirecting Cell Fate
A chemical cocktail of small molecules shows promise in driving neuro-regeneration.
Jonathan James | | Quick Read
Neuronal cell death is a hallmark of several neurological disorders, including Alzheimer’s disease; but translating that knowledge into effective treatments has proven to be a considerable technical challenge (1). Gong Chen, Professor of Biology and Verne M. Willaman Chair in Life Sciences at Pennsylvania State University, is one of those pursuing a new direction: using a cocktail of small molecules to turn astrocytes into neurons. Driven by the belief that mainstream approaches to Alzheimer’s – the most prevalent neurodegenerative disorder – have failed, Chen believes the way to tackle the real underlying aspects of the disease is by replenishing the degenerated neurons. “I don’t think that the past 100 years have missed the main cause in terms of triggering Alzheimer’s disease,” he says. “The real problem is that by the time Aβ and tau plaques are removed, they’ve done enough damage to the patient’s brain by driving neuronal death and degeneration. Without generating functional new neurons to replace the lost neurons, it is difficult to restore the lost brain functions.”
In 2015, Chen and his team unveiled a cocktail of nine small molecules capable of modulating the activity of multiple signaling pathways in astroglial cells, allowing them to be reprogrammed into functional neuronal cells (2). For Chen, however, this breakthrough was not enough. “I knew that it was only a starting point – nobody is going to use nine molecules in a therapy,” he says. “It would be difficult for the pharmaceutical industry to package that many molecules into one pill efficiently.”
So how many molecules are essential when it comes to the process of reprogramming? “We looked at the single molecules – none of them were able to change one glial cell into a neuron,” says Chen, “We could generate some change by combining two drugs together, but the efficiency was too low. Realistically, the minimum is three molecules; by altering three signaling pathways we can alter cell fate.” Chen and colleagues set about looking into the long list of combinations – a slow process – but the group’s recent publication in Stem Cell Reports represents a success (3).
“The three or four molecules we are working on need to be further tested for toxicity and efficacy. Doing so will involve serious collaboration with chemists, perhaps involving chemical modifications to our molecules,” he says. “The goal is to package the molecules into a drug pill that we can administer orally but, to do that, we have to overcome a number of challenges; most notably ensuring that the drug has the right pharmacological properties without causing damage to vital organs such as the heart, lung, and liver.”
Treating neurological pathologies comes with an extra consideration – the blood-brain barrier. Chen is quite confident that the problem can be overcome; “I do have some ideas that will need to be tested,” he says. “But most likely we’ll look for collaborators with expertise in the field – such as Professor Robert Langer at MIT, who I’ve already had preliminary discussions with – to build on our work and make it viable in patients.”
Alzheimer’s is not the only disease in Chen’s sights. “We’re now working on brain cancer, looking at ways we can convert cancerous cells back into normal cells,” he says. “This approach could be even more broadly applied – as we develop chemical cocktails capable of reprogramming cells, all manner of pathologies involving cell loss or cell malfunction could be targeted.”
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- M Fricker et al., “Neuronal Cell Death,” Physiol Rev, 98, 2, 813-880. (2018) PMID: 29488822.
- L Zhang et al., “Small Molecules Efficiently Reprogram Human Astroglial Cells into Functional Neurons,” Cell Stem Cell, 17, 6, 735-747, (2015) PMID: 26481520.
- J C Yin et al., “Chemical Conversion of Human Fetal Astrocytes into Neurons through Modulation of Multiple Signalling Pathways,” Stem Cell Reports, [Epub ahead of print] (2019). PMID: 30745031.