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Ultimately, the majority of us want to find new treatments for patients with neurologic diseases. We’ve had some really brilliant targets in rodent models that have gone on for drug development, and when you get into the human patient population, these drugs just aren’t working.
The question is why?
Is the brain just so much more complex in humans that we’ve missed something important?
Is it so much bigger that we can’t get the drugs in?
Or did we design the drugs for rodent proteins in the rodent system, and they need to be tweaked to work in the human system?
All those possibilities are open questions.
The brain, with its 5,000 different types of cells, is the hardest target for stem cell grafting. It’s a really exquisite network. You can’t just plop in a stem cell and hope that it’ll figure out what to be, how to network and with whom. Many of these directions are present during development when we are young, but may be gone in those of us who are older.
In the lab, we’re trying to figure out what are the cues and instructions you have to give these cells to nudge them along to become the kind of cells or tissues you want in the end. The motor neuron cues have been teased out nicely. And even though we’re good at coaxing stem cells to become neurons and glia, we don’t always get what we want; it isn’t entirely understood about what determines a cell’s fate. Studying this involves taking these cells one step forward at a time and noting the differences in their genetic profiles and their protein composition, among other things.
There’s lots of work, still.
And there are many possibilities for stem cell technology to be useful in advancing medical treatment beyond functional transplantation. It might be that we can use stem cells as drug delivery vehicles. With some neurologic disorders, if you can design a stem cell that pumps out growth factors on command, you might initiate recovery of damaged tissue. This kind of cell doesn’t have to integrate or network with others in the nervous system, because it’ll simply be acting as a drug pump.
In terms of stroke, a goal in our laboratory is to figure out how the brain naturally protects itself, and ask how can we enhance and induce that protection. All our work to date has been performed using rodent cells. Because the work requires live neural tissue, we have not previously been able to explore these events in human tissue. Now, with stem cell technology, we can generate human neural cell cultures, study these pathways in a human system and generate drugs that act on human protein in human neurons. We don’t know if the rodent models are identical to the human condition but suspect that conducting our studies in the human tissue would advance medical discovery faster than a non-human model. At the very least, working in human tissue can be used to validate observations made in non-human systems that are, for the time being, a bit easier to work with.
Another opportunity is in understanding Parkinson’s disease in order to develop new treatments. In general, mice do not get Parkinson’s disease with the full spectrum of pathology or behavioral deficits. Although they have been valuable models, we look forward to being able to generate human neural cultures from reprogrammed patient cells to study this disease.
We don’t yet know what these studies will tell us about the disease but this is the first opportunity we have had to study functional neurons derived from a patient with Parkinson’s disease and explore how they are different healthy control neurons. The hope is that these studies will provide new opportunities to develop treatments for this common neurologic disorder.
--Interviewed by Maryalice Yakutchik