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James Barrow on Developing New Treatments for Psychiatric Illnesses

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James Barrow on Developing New Treatments for Psychiatric Illnesses

Interviewed by Sarah Head

James Barrow on Developing New Treatments for Psychiatric Illnesses

James Barrow is an associate professor of pharmacology and molecular sciences. His team translates basic research on the causes of mental illness into new pharmacological targets for future medications. 

What does your laboratory study?

BARROW: We identify new targets and strategies for developing novel treatments of psychiatric illness. In most psychiatric illness, we believe the roots lie in early brain development. My team focuses on translating basic research on the causes of mental illness, like that done by my colleagues at the Lieber Institute for Brain Development, into new pharmacological targets for future medications. A lot of what we do in the lab is developing models we can use to test new compounds, and then based on the lead compounds we get from these screens, we modify them so they are safe and effective in the human body. It’s really a combination of chemistry, biology and pharmacology.

What makes the Lieber Institute for Brain Development a unique place to do research?

BARROW: The institute is neither an academic institution nor a for-profit company; the goal is to incorporate the best aspects of both of those models. Everybody at the institute has the common goal of brain development/schizophrenia research. The idea is to bring diverse skill sets, expertise and perspectives together to reach that goal. There are people doing developmental biology, and others are doing cell biology work, looking at questions like how a neuron forms from a stem cell. And then there are experts in animal modeling, and many people are doing genetics research. The institute has a very large post-mortem human brain collection that is extremely well characterized across life stages, matched with hundreds of individual skin and stem cells. We also have clinicians designing clinical trials and neuroimaging studies. We can link all these things together to work backward and forward, to shed new light on these very difficult-to-study diseases.

You spent several years working in the pharmaceutical industry. Why did you decide to come back to academia?

BARROW: I was getting frustrated with the very rapid changes of direction. Industry is a great place when what you want to do and what the company wants to do are the same thing. Then you’re able to move fast, get lots of resources and have all sorts of great collaborators. But when they put the brakes on, you’ve got to stop what you’re doing and try to push it back the way you want it to go. At the institute, I have more control over what we are doing and can remain focused on the goal.

How did you get interested in studying schizophrenia?

BARROW: I studied pure organic chemistry, and then when I joined Merck, I did medicinal chemistry. When I started, I was doing blood coagulation and cardiovascular-related projects, which slowly morphed into neuroscience. I really liked the neuroscience, just because there’s so much interesting pharmacology and it’s not as straightforward, so there are a lot of fun puzzles to figure out. I was doing several schizophrenia projects, so it was a really natural step for me to come here.

What’s the approach you take to studying such complicated diseases in the lab?

BARROW: We’re trying to use human genetics to guide what we do. In a way, schizophrenia is kind of like cancer, in that there are lots of different kinds of cancer, and even lots of different kinds of lung cancer, and maybe even in one tumor there’s more than one tumor type. No two individuals with schizophrenia are quite the same—some have more delusions, some have more cognitive issues, some have more negative symptoms. Similarly, there’s no one single mutation that seems to drive it. It’s a combination of many contributing factors, including environmental factors. If we can use human genetics to pin down a target, we can increase our probability of success by focusing in on those who are genetically more likely to respond to a particular treatment.

How do you see treatments for psychiatric illness evolving in the next 10 years?

BARROW: Treatments have to be personalized. Cancer is really leading the way there, in that a lot of cancer drugs now have a companion diagnostic to identify which people are going to respond. The challenge in psychiatry is to diagnose patients more precisely. This will require more discoveries about the biology of the brain so diagnoses can be biologically and behaviorally based. We hope to figure out over time how to put people into well-identified categories and to refine drug selection and dosing based on an individual’s biology.

Will patients in the future have their genome sequenced to identify which treatments will be more or less effective for them?

BARROW: Right now, if we wanted to sequence everybody’s genome, we could. It is almost feasible based on cost. But the question is, what would we do with that information? I think the answer is going to come with time as we find out more about which genetic variants are the primary actors in response to treatment. 

What have you found to be the most challenging aspect of neuropharmaceutical development?

BARROW: There are two things. The one you hear a lot about is getting compounds through the blood-brain barrier and into the brain. We’re getting better at that, but sometimes it’s easier, and sometimes it’s more difficult, and we’re not exactly sure why. The bigger challenge is that the human brain is such a complex organ. When you talk about a liver, most of the liver is made up of cells called hepatocytes, and you can take out a single hepatocyte and study it. The brain has many different kinds of neurons, plus glia and astrocytes, and studying just one cell or even type of cell may not reveal much about behavior. We also can’t really biopsy a brain to get tissue or cell samples. This makes it very challenging to develop a model for how the brain works as a whole.

What’s the most rewarding part of this research for you?

BARROW: The work is not incremental. If you succeed, you’ll succeed big, with lots of people, and the impact will be, I hope, pretty huge. That’s the rewarding part—knowing that mental illnesses affect people in pretty horrible ways, and we can help change that. I’ve gone on rounds in the psychiatry department and met the people we’re trying to treat. Anything you can do for these people is really powerful.

What advice would you give to aspiring scientists?

BARROW: You have to do something you really enjoy doing. It can be so frustrating when you hit obstacles—you beat your head against the wall for weeks, often months, on end. But then you have that breakthrough and it works, and you’re really excited, and then you go off to solve the next problem. To get through the frustrating parts, you’ve really got to love what you do.