Platforms for Proteins

Graduate student Orrin Stone is creating molecular tools to pinpoint how and when cellular pathways trigger cell movement – or, in cancer, metastasis.

Orrin Stone/Photo by Max Englund, UNC Health Care
Cells tagged fluorescent red indicating that Orrin Stone’s prototype “tool” is fused to the protein he studies.

Every day, in every one of us, a few normal cells acquire mutations that turn them into cancer cells. Luckily, our immune system quickly eats these cells. We’re none the wiser, and we don’t get cancer. But as we age and as these mutations accumulate – or if these cellular mutations occur in a sequence that our immune systems don’t recognize as problematic – we do get cancer. And we need some sort of therapy to combat the disease.

In Hahn’s lab, Stone’s project is to build a “platform” so that many new molecular tools can be designed quickly to help scientists better understand cancer cells. At the crux of his research is a basic premise: to understand precisely how cancer cells manage to move from one part of the body to another. Armed with that knowledge, scientists could target the precise mechanisms cancer cells need to metastasize – the major cause of death for cancer patients.

We sat down with Orrin for a student profile about his research project, how he became interested in science, why he chose UNC, and what he hopes the future holds for him and for cancer patients desperate for better therapeutics.

Name: Orrin Stone

Birthdate: August 1, 1989

Hometown: Apple Valley, Minnesota

Education: BS in biochemistry, Seattle University; PhD student, pharmacology

Mentor: Klaus Hahn, PhD

Extracurriculars: camping, hiking, snowboarding; co-chair cytoskeletal club.

Why science?

“I was always interested in science as a kid, but it wasn’t the biggest thing in my life. I was more interested in history and civics. I was on the debate team in middle and high school. I thought I wanted to be a lawyer. But during my later years in high school I took a biology class and a chemistry class with really great teachers who got me interested in this tiny, hidden world that exists in all of us.

“I thought it was really fascinating, particularly the biochemistry section of my biology class, where the focus was on proteins, which are these tiny machines that essentially make all of life possible. So I majored in biochemistry in college. I thought it was amazing that we could understand, at a very detailed mechanistic level, how proteins do these jobs in our bodies, whether it’s making cells move or making cells grow or whatever. I was just amazed that we actually understood these things.”

Undergraduate research?

“I was in a program where all undergrads had to do research. I was in a lab run by Patrick Murphy, a pharmacologist who focused on hormone signaling – specifically, a group of hormones called glucocorticoids, which tamp down the immune response when a patient gets an organ transplant, for instance.

“When I was a junior, my project was to set up this new piece of technology we needed to purify proteins. I wrote a methods paper that detailed the protocol for this machine. I also learned a bunch of really integral methods that are used in the lab a lot– gel electrophoresis, western blots, quantifying protein concentrations. It gave me a good foundation for what I do now; I still use all these methods.”

Why UNC?

“I loved doing research, and as I was thinking about grad school, I talked to [Murphy], and he suggested pharmacology because he said it would give me a lot of opportunities down the line. I looked online and talked to people about pharmacology graduate programs, and UNC kept popping up again and again as one of the best programs in the country.

“I applied and got in. It was my first choice from outset because UNC had the best diversity of pharmacology research. I didn’t know exactly what I wanted to research when I came down here. It was all very interesting to me. A lot of other programs were more narrowly focused. But here, there were pharmacologists studying neuroscience, cancer, basic cell biology.

“Also, the research here is really high caliber and there’s great funding. People are really committed and passionate about what they do. And during my interviews here, the grad students I met were great.”

Why Klaus Hahn’s lab?

“Even before I got to UNC, I went on the UNC pharmacology website to look at the different kinds of labs here, and I remember looking through Klaus’s website and seeing videos of cells. I thought, ‘what’s this about?’

“In these videos, they could both visualize and control specific pathways in moving cells.”

“So even before I even understood the biological questions they were answering with these tools, I thought this stuff was just really cool. I couldn’t believe you could do this. So I started reading his papers and saw that they were doing something that very few labs had ever done before – actually looking at cellular signaling pathways and manipulating them on the same time scales in which they operate.

“Normally in cells these pathways get turned on in seconds and can get shut off a minute later. People have studied these pathways before, but they studied them with tools that work over the course of a day. From this, you can get a general idea what a given pathway might do, like whether it might play a role in cell migration or division, but they’re not really suited for understanding these pathways at a detailed level.”

The overall research goal?

“My dissertation focuses on developing new tools, especially a platform that enables more efficient and more rapid development of tools to study timing and localization of signaling during cell migration, which is really important for many diseases, including cancer and autoimmune disorders – diseases that involve cells moving from one location to another. This movement is intimately tied to the progression of disease.

“Artificially, we can turn on a pathway across the whole cell and that will give us a rough idea of what that pathway does. But that’s not how these pathways work in the body. Many of them don’t get turned on all day; they’re turned on for maybe minutes and then shut off. And they’re turned on in a specific location in a cell, not across the entire cell. So we need to know where and when that activation happens so we can understand how that pathway fits into the broader architecture of the cell.

“This is important because there are tons of pathways involved in cell migration. So just knowing that a pathway is involved in migration doesn’t really tell us a whole lot about what it actually does and when. We need to know that – especially relative to when other things are turned on – if we’re really going to achieve a mechanistic understanding of these pathways. This is how we’ll begin to understand how cells actually move or migrate or divide.

“This is the next level of detail we’re trying to get to because, in cancer for instance, the vast majority of deaths occur because cancer spreads throughout the body.

“Another example is rheumatoid arthritis. For whatever reason, your immune cells move into joints and attack your own cells. So again, it’s the misregulation of cell movement. We want to understand how these ‘movement’ pathways work so we can better treat patients.”

Your research?

“Klaus Hahn’s lab has created tools, which involved protein engineering, which can take years. We looked at one target in a cell – a protein – that worked on certain pathways and specifically designed a tool for that protein. This tool allowed us to control this one pathway.

“If we want to get idea of how an entire pathway works or how migration works, we’ll need a lot of these tools to look at a lot of protein pathways in a time-sensitive manner. So my project is, instead of looking at a protein that can help you control ‘this,’ I’m asking if there are shared features of proteins that are similar in how they are regulated. And if there is something that’s shared by a lot of different proteins, can we broadly target that one feature?

“The feature I’m looking at is protein autoinhibition. When a protein is inactive, it’s in a closed conformation. And when activated, the protein opens up.

“I’m trying to exploit that big change from ‘closed’ to ‘open’ to sense the protein activation and control it. If we can develop this platform, then maybe we can quickly and broadly apply it to a bunch of different proteins that are all regulated in a similar way. This, essentially, would expand the amount of tools we have to study these pathways and hopefully get a better understanding for how they all work.”

The future

“Ultimately, I want to start my own lab, but to do that I’ll have to do at least one postdoctoral fellowship, maybe two. I’d like to go to either Stanford or UC-San Francisco; there are several labs out there doing similar work to ours, and they’re focused on some of the biological questions I’m really interested it.

“This is where I think the tools we’re working on will be really important. It’s called cell-based therapeutics. Therapeutics for diseases have typically been drugs. In some cases, biologics – antibodies people make. Lots of new cancer treatments are actually antibodies.

“What’s really new is the use of whole cells, themselves, as drugs.

“So when you get cancer, it’s really a failure of your immune system to target these cells and fight them. So in a small trial researchers took blood from cancer patients, isolated certain immune cells, and reengineered them to make the cells more efficient at fighting cancer. Then the doctors put the immune cells back into the patients so they could more effectively fight the cancer.

“I want to get involved in engineering cells to fight other diseases. A couple labs at UC-SF are laying the groundwork – doing the basic science – to make this all possible in the future. I think that’s a really exciting area to get into.”

Stone’s mentor, Klaus Hahn, PhD, is a member of the UNC Lineberger Comprehensive Cancer Center.

Media Contact: Mark Derewicz, UNC School of Medicine science communications manager, mark.derewicz@unchealth.unc.edu

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