Anyone lucky enough to be invited over for lunch with postdoctoral fellow Fatma Zehra Yildiz of Victoria D’Souza’s lab should accept immediately. Whoever does will be treated to delicious, homemade, traditional Turkish food, with portions so large they will be pressed to take some home.
Yildiz learned her culinary skills growing up in Istanbul, Turkey, where her father worked as a professor of Naval Architecture and Marine Engineering. It was her father who inspired her to think about a career in academia, though her own circuitous route would bring her to structural biology and research on retroviruses instead of engineering.
“He was always working on his book or papers,” Yildiz said. “I just admired my father, without knowing too much about what his studies are about.”
She says while at high school, she did not fit in with the popular kids, but instead put all her energy into studying as a quiet student. The benefit of her hard work was a high enough score on her national university entrance exam to get into faculty of pharmacy at Istanbul University right after high school, at a time when there were only seven universities with faculty of pharmacy in Turkey. However, her rebellious streak in certain areas affected her relations with professors.
“I follow a certain dressing code, part of which is a headscarf, due to my religion,” she said. “It’s my personal choice. But at the time, some of the Turkish government’s policies were not the most civilized ones, and it affected me a lot because it used to be forbidden to wear a headscarf within the vicinity of universities and other state-related buildings. Because of this, a majority of the professors at my department were not friendly to me.”
Yildiz admits that while wearing a headscarf was not essential to her way of life, the idea of being barred from doing something that she had freely chosen to do went against her nature. Looking back she says she is not sure If she made the best decision to fight against university policies, but at the time she could not reconcile herself to their standards. She decided to take a year off from college, and attended street protests almost the entire year, hoping that the situation would improve. Unfortunately, it got worse, and her father encouraged her to go back to college.
“It is not about not showing my hair, it’s not that,” she said. “It was about why are you forcing me to think and act in a way that I don’t agree with. Simply I couldn’t come to terms with it, so I and several of my friends facing the same problem all shaved our heads or wore funny wigs to protest this rule.”
“When I graduated from college, I had to deal with the consequences of those years of struggle on me,” she said. “I was heartbroken with the government, never with my country. But the good thing is despite it all, I was not giving up.”
Yildiz’s studiousness failed to impress the graduate administrators in Turkey, who were still hung up on her appearance. At that time her friend, who would later become her husband, was a graduate student in California, and he encouraged her to apply to grad schools in the U.S. She was accepted to the University of Maryland, Baltimore County, where she eventually began working in the laboratory of biochemist Michael Summers, an HHMI investigator working on the structural biology of retroviruses.
“Other than being an incredible scientist, he was a very welcoming, very open-hearted person,” she said. “One day he was giving a tour of his remarkably huge lab to a group of people, and I was doing my work as a rotation student. He said to them that besides his science, he was most proud of the diversity of people in his lab from different backgrounds and cultures. I overheard it and said I want to stay in his lab.”
During her graduate work, Yildiz focused on how retroviruses specifically recognize and package their genetic material during one of the late stages of retroviral infection, using bovine leukemia virus (BLV) – a model for HTLV-induced leukemogenesis in humans.
“Retroviruses carry a dimeric RNA molecule as their genomes, and genome recognition is a critical step in their life cycle,” she said. “Genome recognition is mediated by specific interactions between nucleocapsid (NC) domain of the viral Gag polyprotein and viral RNA elements residing within the 5′ end of the genome, namely the packaging signal. When they recognize each other they bind, and this initiates genome packaging.”
“As a PhD student in Summers lab, the aim of my project was to identify and structurally characterize a high affinity NC protein binding RNA element within the BLV RNA packaging signal,” she said. “I am also a structural biologist so I used nuclear magnetic resonance (NMR) spectroscopy to elucidate the atomic level resolution of this RNA element with and without the NC protein bound to it.”
Some of these findings were published in the journal Virus Research in 2013, and the rest of her findings are to be submitted soon. But when she came to Harvard and began working in the D’Souza lab, her focus shifted from a late stage of the retrovirus life cycle to reverse transcription initiation, an early phase event. Reverse transcription is the hallmark of the retroviridae family, and its initiation is highly specific. The work had been started in the lab by D’Souza’s former student Sarah Miller. Miller and D’Souza’s submission to Nature had been returned with revisions asking for a lot more experiments, but since Miller had already left Harvard, Yildiz was asked to finish the work.
“When a retrovirus infects the cell it releases its core, after which the reverse transcriptase enzyme initiates reverse transcription from a highly specific RNA complex,” she said. “This RNA complex is formed upon annealing of a specific host tRNA molecule to a specific region of the viral genome by the chaperone activity of the NC protein. The result of this is the formation of the preintegration complex (PIC), which then goes into the nuclease for integration of the viral genome into the host cell.”
It took Yildiz over two years to finish the rest of the work, and their findings were finally published in Nature: Letters in November 2014. In this work, the authors showed the first structure-based mechanism for tRNA and retroviral RNA remodeling by providing detailed structural views of the two RNAs as they were being remodeled by murine leukemia virus (MLV) NC proteins. This turned out to be an elegant new mechanism for RNA remodeling that is distinct from the mechanisms utilized by other known RNA chaperones and remodelers.
The goal of Yildiz’s current project is to solve the structure of the reverse transcription initiation RNA complex of HIV-1, and to elucidate its features that are specifically recognized by the reverse transcriptase enzyme.
“Scientists in the field have been trying to solve the HIV-1 reverse transcription initiation complex structure for almost three decades,” Yildiz said. “However, they haven’t been able to obtain crystals with good diffraction, probably due to presence of flexible regions. NMR, on the other hand, was not easily applicable for solving such big RNA structures [around 60KD]. However, recent advancements in NMR pulse programs and a variety of novel sample preparation techniques now could allow solving such structures by NMR, even though it still comes with a lot of challenges.”
Traditionally, anti-HIV drugs, like protease inhibitors, have targeted viral enzymes in order to slow the progression of the disease, eventually disrupting the life cycle at certain points where these viral proteins play critical roles. However, the adaptability of the virus has limited the effectiveness of this approach.
“Even though these antiviral protein drugs were effective on patients with AIDS for a while, they started to loose their effectiveness over time due to emergence of newly evolved HIV strains that are resistant to these drugs,” she said. “Even targeting multiple stages of the viral life cycle simultaneously with a combination of several different protein inhibitors, a strategy known as highly active antiretroviral therapy (HAART), does not entirely solve this problem.”
Yildiz is one researcher whose work could eventually contribute to a different strategy: targeting the viral RNA-protein complexes.
“RNA elements within the 5’UTR [untranslated region] of viral genome fold into highly complicated structures,” she said. “These structures interact with several viral or host proteins while directing multiple crucial roles at various steps of viral life cycle. Since 5’UTR sequences are also highly conserved among different strains, if you can design a drug that interferes with such RNA-protein complex structures, it would create an additional target to combat the virus.”
Yildiz considers herself very lucky that she has hit upon an area of research she absolutely loves. She says that although she would certainly love to find treatments for retroviral diseases, her real motivations are simply her love of science and her gratitude toward the PIs who influenced her and celebrated diversity in their labs. She also feels a responsibility for passing her knowledge to the next generation.
As soon as her paper is accepted, Yildiz will begin applying for positions in the U.S. and Europe.