Profiles in discovery

From the Fall 2019 edition of Vanderbilt Medicine Magazine

Infectious diseases. Addiction. Mitochondrial diseases. Glioblastoma.

In this issue of Vanderbilt Medicine, we share glimpses of five basic scientists in the early stages of their careers who are tackling these tough clinical problems by probing structures of individual proteins, cell identity, signaling pathways and animal decision-making behaviors.

They are part of Vanderbilt University School of Medicine, Basic Sciences, an integrated research and education division within the School of Medicine that includes four academic departments, eight interdisciplinary centers, 20 service core facilities and the Office of Biomedical Research Education and Training.

More than 1,000 faculty, fellows, students and staff are making basic science discoveries every day at Vanderbilt — discoveries that are building the foundation for clinical advances in preventing, diagnosing and treating human diseases.

These are some of their stories.

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Photo by John Russell

In one of the classes that Manuel Ascano, PhD, teaches to graduate students, he shows a slide with two long sequences of RNA.

“I ask if anyone in the class can identify the first or second sequence, and of course they can’t. The sequences just look like random stretches of ACGUs,” said Ascano, assistant professor of Biochemistry, referring to the chemical bases that compose RNA — the messenger of genetic information encoded by DNA.

Somehow though, he tells the students, proteins in our cells “know” that the first sequence is from the bacterium that causes cholera and the second is from human tubulin.

“How do these proteins know? This is the core curiosity that drives our research,” Ascano said.

Ascano and his team are looking for proteins that respond to RNA viruses at the earliest moments of interaction between virus and cell. And they’re doing it in a unique way, using new technologies they’ve developed to isolate and identify RNA-binding proteins.

Of the 260 or so viruses that are known to cause human disease, about 60% use RNA instead of DNA as their genetic material. These include viruses that cause flu, Ebola, HIV and SARS.

“These viruses are basically RNA wrapped up in a package,” Ascano said. “Our tools are made for exploring this moment of ‘first contact’ between the incoming viral RNA and the proteins that will recognize the virus and shut it down or be fooled and hijacked for the virus’ use.”

The son of two physicians, Ascano grew up in Queens, New York, listening to dinner-table discussions about science and medicine and watching videos of surgeries with his dad. During college at the University of Illinois at Urbana-Champaign, his interest in medicine shifted to scientific discovery.

“I realized that I wanted to be working ‘upriver,’ at the source of the discoveries,” Ascano said.

He earned his PhD in biochemistry from the University of Cincinnati and studied RNA biology during a postdoctoral fellowship at The Rockefeller University.

Along the way, he contributed to a basic science discovery that has moved rapidly to a drug being tested in phase I clinical trials. He and his colleagues at Rockefeller found a unique chemical bond in the product of an enzyme that senses foreign DNA in the cell and activates the protein STING, which fires up the innate immune response. The “enzymatic quirk” they discovered has informed efforts to develop a new class of cancer immunotherapy drugs.

“I was looking at this from a purely basic science perspective. It’s humbling to see something you’ve discovered end up in the clinic,” Ascano said. “I don’t expect that to happen very often, but it’s great when it does.”

Ascano joined the Vanderbilt faculty in 2014. He and his wife, Janice, also a PhD-trained scientist, have two children.

 

 

Photo by John Russell

Erin Calipari, PhD, is not intimidated by the complexity of the human brain. She’s trying to understand the neural circuits that control motivation and decision-making.

“I know that the brain is complicated, but I think it’s made up of a series of predictable events,” said Calipari, assistant professor of Pharmacology. “We’re studying at the cellular and molecular level how animals make decisions to seek rewarding stimuli and avoid negative stimuli, and how exposure to drugs of abuse dysregulates that code.”

Calipari discovered her passion for science when she was a student at the University of Massachusetts. She loved one of her science courses so much that she turned in a 20-page experimental design proposal for a “fun” end-of-course project. The professor promptly invited her to do research in his laboratory, which focused on drug abuse in animal models. She was hooked.

“It was the greatest thing, and I ended up spending so many hours in that lab,” Calipari said.

The experience prepared Calipari for graduate studies at Wake Forest University, where she explored drug addiction in behavioral animal models and analyzed neurotransmitter release in the brain using analytical chemistry techniques that she and her colleagues developed.

During her postdoctoral fellowship at Icahn School of Medicine at Mount Sinai, Calipari expanded the range of technologies she uses — both in brain tissue and in awake and behaving animals — to probe the neural circuits underlying drug abuse and addiction.

“I try to ask really good innovative questions and to use new technologies … to take us a step further than we’ve been before,” said Calipari, who joined the Vanderbilt faculty in 2017. “That’s part of the fun of science — you always get to do something new.”

Calipari is excited about recent discoveries in her laboratory examining sex differences in drug abuse vulnerability. Using animal models, she and her team have found that estrogen increases the brain’s cocaine reward signaling and makes females more likely to respond to “cues” that lead to relapse. The findings may point to different processes for drug addiction in men and women and suggest the need for different treatment strategies.

As a member of the Vanderbilt Center for Addiction Research, Calipari values being in close proximity to clinicians and patients.

“We’re studying the basic mechanisms of how the brain works and how organisms make decisions, and we’re doing this in the context of a disease process that’s critical for public health,” she said. “We look forward to working with our clinical colleagues to move basic science discoveries into translational studies.”

In her free time, Calipari enjoys rooting for the University of Kentucky men’s basketball team, coached by her father, John Calipari.

 

 

Photo by John Russell

Breann Brown, PhD, likens her structural biology research to a jigsaw puzzle, where individual proteins are the puzzle “pieces” that fit together to perform cellular functions.

By focusing in on the details of the proteins — their bumps and crevices — Brown hopes to put together a full picture of the physiology of mitochondria, the “power plants” of the cell. Genetic mutations in the mitochondrial proteins she studies cause blood disorders and early-onset neurodegenerative diseases.

“We’re looking at how mutations alter the structure of the proteins and their interactions with other proteins to understand how it all fits together,” said Brown, assistant professor of Biochemistry.

Her team uses X-ray crystallography and other complementary biochemical techniques to explore protein structure and function.

Brown didn’t set out to be a structural biologist. She remembers declaring at the start of graduate school that she would never do X-ray crystallography because “it seemed so difficult and abstract,” she said. When one of her preferred laboratory rotations wasn’t available, she ended up with an alternate rotation in a structural biology lab.

“The project really interested me, but I was completely afraid of the technique,” she said. “I found out that you learn X-ray crystallography just like you learn anything else. It helped that I’m very stubborn, and if I decide I’m going to do something, I’m going to do it.”

Brown grew up in the Maryland suburbs of Washington, D.C., and was always drawn to science and math, she said. She attributes her interest partly to her mother’s work as a pharmacist.

She studied chemistry and pharmacology at Duke University and then earned a PhD in molecular pharmacology and physiology at Brown University, where she studied proteins involved in multi-drug tolerance. She completed a postdoctoral fellowship at the Massachusetts Institute of Technology and joined the Vanderbilt faculty this year.

As the only African American tenure-track professor in the School of Medicine, Basic Sciences departments, Brown looks forward to participating in initiatives to increase diversity at Vanderbilt, and she stresses the importance of also focusing on inclusion.

“Just getting people in the door doesn’t help if there’s no community to help them learn and grow and build a research program,” she said. “It takes candid discussions and a willingness to challenge stereotypes to get to a place where we can really take steps to grow the School of Medicine and the University.

“I know that I’m here because I’ve had really good mentors who have supported me and my career goals. Now part of my job is to provide that same kind of mentorship to other people.”

 

 

Photo by John Russell

Rebecca Ihrie, PhD, and Jonathan Irish, PhD had the idea in mind for a long time — that at some point, they might be able to combine their unique research skills to study aggressive brain tumors in a way that no one else could.

First, they built independent research programs: Ihrie focuses on understanding brain stem cells and their relationship to brain tumors; Irish develops new tools to study signaling networks in single cells.

Now, with collaboration from neurosurgeons and neuropathologists, and with key investments by Vanderbilt, the two assistant professors of Cell and Developmental Biology are working together to explore the biology of single cells from glioblastoma tumors removed from patients.

The pair, who met as undergraduates at the University of Michigan, were graduate students in cancer biology at Stanford, and got married along the way, wanted to work on difficult cancers in need of new scientific discovery and interventions.

“Glioblastoma is at the top of the list,” Ihrie said. “The standard of care and the median survival has remained relatively unchanged for more than a decade.”

For Irish, brain tumor research is also personal. His father died from glioblastoma while Irish was in college.

“Seeing him go through a one-size-fits-all sort of treatment really shaped my thinking about cancer,” Irish said. “Wanting to match the treatment to the tumor cells has been something I’ve been working on for my whole scientific career.”

As a graduate student, Ihrie studied the tumor suppressor gene p53 and its function in mouse models. For postdoctoral training, she selected a research group that had discovered stem cells in the adult brain and was part of a neurosurgery department.

“I wanted to be able to collect and analyze human tissue so that I could study the exact thing I was interested in,” Ihrie said.

At Vanderbilt, Ihrie and her group have focused on a neuron-generating “stem cell niche” in the brain. They discovered that glioblastoma tumors that are in contact with the stem cell niche — a feature that is visible on MRI — have worse outcomes, and they are working to understand tumor cell-niche interactions.

For his graduate studies, Irish joined a technology-focused lab, where he used flow cytometry of cell samples from patients with acute myeloid leukemia to characterize and link cell signaling to patient outcome. He wrote software to analyze the flow cytometry data, and later as a postdoctoral fellow co-founded a company to support the software. The software continues to be used, and the company, Cytobank, was recently purchased by Beckman Coulter.

At Vanderbilt, Irish has led the development of mass cytometry, an analytical flow cytometry technology capable of measuring more than 40 features of individual cells. He and his team have perfected methods for applying single-cell approaches to solid tumors, such as brain tumors.

Ihrie and Irish used their combined expertise to analyze single cells from glioblastomas in an “unsupervised” way.

“We’ve applied machine learning tools to classify the cells and look for patterns in the biology,” Irish said. “Then we asked, ‘Are any of these cells that we’ve revealed associated with good or bad outcomes when they’re found at a high level in someone’s tumor?’”

The short answer: yes.

If validated, the findings may translate into improved treatments, Ihrie and Irish said. The cells associated with bad outcomes have a pattern of cell signaling that points to possible treatments not previously considered for glioblastoma. The cells associated with good outcomes come from tumors with more immune cells and may be a signature for patients who would benefit from immunotherapies.

Ihrie and Irish credit Vanderbilt with giving them the freedom to pursue an unusual experimental approach — by investing early in mass cytometry and by helping them secure pilot funding from discovery grants and foundations.

“We’re the only people in the world who have the team, the samples, the instrument and the expertise to do the studies we’re doing,” Irish said. “Vanderbilt is well-positioned for some exciting types of brain tumor research.”

The busy scientists, who joined the Vanderbilt faculty in 2011, can sometimes be found on weekends at a local skate center, roller-skating backward with their two young sons.

 

 

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