Moriah Katt: Breaching the barricade
Moriah Katt’s artificial model of the blood-brain barrier’s cells and vessels is like an ant farm. A working replica of the vascular system separating the brain from the body, Katt’s model allows her to see and manipulate the inner processes of that almost impermeable membrane.
Research Community Spotlight Series: Written by Micaela Morrissette, WVU Research
Photographed by Matt Sunday
"I’m especially interested in diseases of the central nervous system because blood vessels in the brain are a little bit special and different than blood vessels elsewhere."
Rigorously controlling what passes through its vessels, the blood-brain barrier both protects the brain and blocks the delivery of life-saving drugs for patients with ischemic stroke, Alzheimer’s disease and brain tumors. Katt’s research is part of a global effort to get treatments across the barrier.
A biomedical engineer, neuroscientist and assistant professor at West Virginia University's Statler College of Engineering and Mineral Resources and Health Sciences Center, Katt comes at the problem from two directions at once. She takes an “in vitro” approach – creating a mechanical environment and growing cells to simulate conditions within a body — and an “in vivo” approach: conducting parallel experiments in a live animal model. The crosstalk between these methodologies will drive Katt’s quest to find an antibody that can penetrate the blood-brain barrier, transporting therapeutics into the brain.
Q: How does this research work?
A: My lab makes artificial brain blood vessels to look at how we can get therapeutics across those vessels and into the brain. I’m especially interested in diseases of the central nervous system because blood vessels in the brain are a little bit special and different than blood vessels elsewhere. The brain’s blood vessels do an excellent job restricting almost everything from making it into the brain, which is important for normal brain health but very problematic when you're trying to deliver a therapeutic into the brain. You essentially can't get it there.
We make a microfluidic model of these blood vessels in the blood-brain barrier, using a tube in the middle of a collagen type I hydrogel and lining that tube with endothelial cells to see how cells respond and how we can transport therapeutics. We simulate blood flow using a cocktail of proteins, salts and media.
The cells in your brain will be there for essentially your whole life. There's no regeneration, no cell renewal, so getting human brain cells to work with is difficult. We use human-induced pluripotent stem cells that we bring through multiple differentiation pathways to end up with the endothelial cells, neurons or other cells we’re interested in. One of the beauties of this system is that because we grow our endothelial cells from human stem cells, the expression of transporters should mimic human tissue more closely than rodent tissue does.
Q: How does the rodent research relate?
A: Some of the animal techniques happening at the Rockefeller Neuroscience Institute are truly extraordinary. You don't find these animal models at every university. My expertise is in vitro models, so I’ll work with WVU animal model experts Jason Huber and Werner Geldenhuys, doing parallel experiments: how things behave in my human in vitro model, then how they behave in the animal model.
Maybe we’ll see something happening in the animal model but don't understand why – there’s the benefit of the in vitro model. It's a lot more simplistic, so I can go back and say, “Okay, that’s what we saw in rodents. Why was that happening?” I can narrow in on the mechanistic understanding of what’s going on.
Ischemic stroke, where the flow of blood carrying oxygen to the brain is constricted, is one of the conditions I’m interested in, and in the in vitro model we can more strictly control the changes in flow rates that you see in ischemic stroke, the oxygen conditions and concentrations and the nutrients that flow through. There are a lot more knobs we can turn in the artificial environment, rather than just looking for a yes/no answer in an animal.
Q: Are there other potential applications?
A: One of our model’s advantages is that it's a general model of the blood-brain barrier, not necessarily a model for a specific disease. Right now, the expertise and skills are here to focus on ischemic stroke so that's what we're primarily looking at. But one of the common sites that breast cancer metastasizes to is the brain. There are some scary statistics about the number of people with secondary breast cancer metastases – something like 10% of them are in the brain. Understanding why breast cancer cells hone in on the brain is one of the things I'm interested in long term.
Q: How do you identify antibodies that might be able to carry drugs across the blood-brain barrier?
A: I’m not focusing on attaching a therapeutic to a specific transporter that carries insulin or iron, for example, as some other labs are. I’m not looking for a specific transporter for therapeutics – I’m looking for any kind of transporter. I use a screen of antibodies that could bind to anything on the blood-brain barrier, antibodies that could target anything from a red blood cell to a sugar molecule – I have no idea. My lab will take all these antibodies, unbiased, no prescreening, put them in contact with our cells and ask, “Which of these can be uptaken into the cells?”
In my postdoctoral lab, we identified three interesting antibodies from a lamprey, which is a very odd fish. These antibodies targeted the brain of rodents. They weren’t targeted to the heart, they didn't show targeting to the kidney or liver – these antibodies went specifically to the brain. So there are targets there for this specific brain homing, which is very exciting.
Q: What scientific achievement from history do you wish you could have been there for?
A: I’m obsessed with the blood-brain barrier – it's a very cool space to work in. In the late 1800s, Paul Ehrlich did experiments on dye penetration into cadavers, looking at where these dyes end up. Really weird experiments! He's the person who identified the blood-brain barrier, because he’d inject the dyes and they'd go everywhere, but they wouldn't be in the brain. I’d love to have been there for that.
Contact: Paige Nesbit
Statler College of Engineering and Mineral Resources
304.293.4135, Paige Nesbit
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