By Mark Derewicz
When Catherine Fahey was a high school sophomore, her mother asked her and her sister Kristin to sit with her. She said she had some bad news. Their maternal great-grandmothers both had battled breast cancer. Their maternal grandmother had breast cancer. And then she, at 47, was diagnosed with the disease.
Kristin and Catherine didn’t know what to say. Humor had always been Catherine’s defense against troublesome news. She said, “So what you’re telling us is we’re screwed.”
Her mother gave a hardy laugh. Then she hugged her daughters and talked them through everything that would happen from that point forward – the surgery, the chemotherapy, the hair loss, the tests, the hope.
“I remember we had this Lego version of Yoda from Star Wars,” Catherine said. “My mom used it as a wig stand. My mom is strong; she showed us what a positive outlook really looked like.”
After successful surgery, the prognosis was good. There were no signs of metastasis. After chemo and the passage of time, doctors reported that Catherine’s mom was cancer free.
That was 11 years ago. Mrs. Fahey remains happy and healthy.
“I obviously wouldn’t wish cancer on anyone, but this was a formative experience for me,” Catherine said. “I knew that I would always be interested in cancer in one way or another.”
This year, Catherine – a fourth-year PhD student in the UNC MD/PhD program – received an F30 grant from the National Cancer Institute. She studies kidney cancer. In particular, she studies how the lack of a gene called SETD2 plays a significant role in the development of renal clear cell carcinoma. Now her work and the final two years of medical school will be funded through the NCI.
We sat down with Catherine Fahey for a Student Profile to ask her about her love of research, her focus on oncology, and why the UNC MD/PhD program was the perfect fit for her.
Hometown: Fort Wayne, Indiana
Education: BS in genetics, Purdue University; MD/PhD program, curriculum in genetics and molecular biology
Dissertation: The effect of cancer-associated SETD2 mutations on transcription and chromatin organization
Goal: Understanding how mutations in one gene cause changes to the way DNA is packaged inside kidney cancer cells
Mentors: Kim Rathmell, MD/PhD; Ian Davis, MD/PhD, department of genetics / UNC Lineberger Comprehensive Cancer Center
Extracurriculars: Advocate for UNC MD/PhD Women in Science
The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell, August 2014
A Tale of Two Cancers: Complete genetic analysis of Chromophobe Renal Cell carcinoma contrasts with Clear Cell Renal Cell Carcinoma. Molecular and Cellular, January 2015.
“I remember vividly when I decided to pursue science. I was a junior in an AP biology class I took because the teacher was my favorite. One day he invited a scientist from Indiana University who talked to us about everything new and hot in genetics. Gene therapy was exploding in popularity. This spring, 2005. I had never been so captivated by a talk. I took more notes that class than ever before. At the end of the day, I went to my teacher and said, ‘How do I do that? That’s what I want to do with my life.’
“My mom’s diagnosis is what drew me into cancer research. I wanted to know more about how the basic genes that make us who we are can turn against us and turn cells into cancer.”
“I was in a cancer research lab, studying the protein BATF. I was trying to figure out if it would work as a tumor suppressor with this other gene – a major oncogene – that is known to make cells grow like crazy. It was really interesting mechanistically, trying to figure out how these two proteins might interact and what that could mean. It was a good project that introduced me to molecular biology and genetic manipulation.
“I was in that lab for four years. I joined it six months into my freshman year and worked there every summer. It was a really great experience that showed me how much I loved research. But I also knew that such basic research wasn’t quite the right fit for me. I needed to do something a little more clinically oriented.
“When I was interviewing, I was really impressed with how much everyone focused on the students. When I tried to decide between programs, I looked at which schools were doing the kinds of research I wanted to do, and none were doing research in cancer biology like UNC. I really wanted to do translational research, which UNC is really great at.
“Also, the MD/PhD program is absolutely fantastic here. The people who run it and the PIs are 100 percent on board with what students want to pursue.
“The faculty is just phenomenal here. The work with the Cancer Genome Atlas is incredible, and UNC is one of the leaders in the country on that. I can’t imagine being at a better place.”
“I planned on going to graduate school, and I really loved what I was doing as an undergrad. But I was also a little frustrated. It wasn’t really clear how our project would inform cancer therapeutics. There’s nothing wrong with that. It was important work; it just wasn’t what I particularly wanted to do.
“Then I found out that doing an MD/PhD was an actual thing. Before that, I really wrestled between research and going to medical school. Ultimately, I thought that getting an MD would allow me to see patients and pull them into my research. A PhD would allow me to pull research into the clinic."
How does an MD/PhD work, exactly?
“The first two years are spent taking medical school courses. There are some opportunities for patient interaction. They send everyone into the community [as part of Clinical Week] to work with physicians across North Carolina. Basically, those first two years, we learned how things typically work in humans and what changes when things go wrong. We also learned how to do an exam so that when we go into the clinic as third-years, we have a foundation to build upon.
“Then you join a lab and do a complete PhD. I’m in my fourth year. After I graduate, I’ll go into my third year of medical school, then my fourth year. Then I’ll match and do a residency.”
Why the labs of Kim Rathmell, MD, and Ian Davis, MD, PhD?
I joined Kim’s lab because I looked through different websites in UNC’s genetics department and the UNC Lineberger Comprehensive Cancer Center, and I felt like her lab matched my interests the best – a lot of molecular biology and cancer biology work. I added Ian Davis as a co-mentor a month into my PhD because my project really sits at the intersection of their two labs. Kim’s lab was a kidney cancer lab.”
[Rathmell left UNC this summer to become the director of the division of hematology and oncology at the Vanderbilt University Medicine Center.]
“Every project in her lab focuses on kidney cancer. And Ian’s lab focuses on chromatin biology. What’s interesting about kidney cancer is that changes in chromatin are really common, and that’s not true of every kind of cancer. So my project is the perfect blend of these two labs. Also, Ian does a lot of bioinformatics work, and it was a great opportunity to learn from him and his team."
What is chromatin?
“Chromatin is the way DNA is packaged in the cells. If you stretch out a strand of DNA end to end, it would be absurdly long – too long to fit inside a tiny cell. So it’s wrapped up inside a cell’s nucleus until you end up with magnitudes of compaction. That’s chromatin.
“But the cell has to use that compacted DNA. So each cell has chromatin regions that are relatively closed down – regions that the cell does not use as much. Each cell also has chromatin regions that are relatively open – these are used more often. One of the things we’re looking at is how the regions that are open relative to closed change when you have kidney cancer.”
What are some results of this work?
“I study SETD2, which is a gene involved in changing the protein that the DNA is wrapped around. SETD2 modifies one of the amino acids on those proteins. I study kidney cancer cells with and without SETD2. These cells are 100 percent identical except for SETD2. It’s a really great system to use to figure out what SETD2 does.
“We found that when you remove this protein, the cancer cells grow faster. We see changes in gene expression.
“We’re still in the early stages of analyzing that data, but we’ve learned that the DNA is relatively more open in tumors that are missing SETD2. The next step is to study this in an animal model. Our lab is currently checking the ability of these SETD2-deficient cells to form tumors.”
What’s the big picture?
“We want to figure out if the changes we see in chromatin – in tumors – are specifically due to the lack of SETD2. And we want to figure out what causes those changes – chromatin being more open versus closed – because there are a couple ways this could be happening.
“Those proteins that the DNA is wrapped around could be moving; they could be changing chromatin accessibility. Or you could have proteins being completely taken off the DNA. Or these proteins could be destabilized somehow. They could be loosely interacting. I’m using two different techniques to look at this chromatin accessibility to find out what exactly happens in relation to SETD2 and kidney cancer.
“This is why I got an F30 NIH grant, which is what they give to MD/PhD students. The graduate student equivalent is the F31.
“Here’s another plug or the MD/PhD program: UNC is one of the best in the country at getting F30 grants.”
Down the road?
“Ultimately the hope is to use this information in the development of therapeutics. SETD2 is lacking in kidney cancer cells. So, perhaps compensating for the loss would be beneficial for patients. We’ve been trying to find a gene or a compound that these SETD2-deficient cancer cells are susceptible to.”
“I really hope that we have a paper ready to go in the spring. If so, then I can hopefully graduate soon afterward. Regardless, once I graduate, I’ll go back to medical school. I anticipate that I will probably love internal medicine – oncology. I very much doubt something else will grab my interest. But you never know what you’re going to like until you actually do it during that third year. I am also interested in OBGYN oncology.
“Long-term, I really want to be a physician seeing patients. Usually, MD/PhDs see patients for a half-day a week. And I’d like to be involved in clinical trials and work in someone’s lab. I’m not sure if I want to run my own lab, but I definitely want to do research.
“I’d love to stay at UNC. That depends on if they will have me. A lot will depend on where I do my residency. After that, I hope to do a fellowship in oncology."
What does your mom think of all this?
“As a kid, I was all over the place. I thought about being a teacher or a lawyer. Being a doctor didn’t come up that often. It’s kind of funny how I stumbled into it, but it is absolutely where I belong.
“My mom likes to laugh about it. She likes to say I always just kind of find my way. But for a while she’s been telling me I should be a doctor. When I was taking organic chemistry in college and telling everyone how much I loved it, she’d say, “Catherine just go to medical school.”
“So she thinks what I’m doing is great. We’ve talked a few times about how much her having cancer kind of directed my life. Of course we all would have preferred that she didn’t get cancer, but I think she’s happy that her disease kind of spurred me along this path. And I am, too.”