Agata Smogorzewska is interested in the processes that prevent deadly errors from accumulating in DNA. It turns out that a rare genetic disorder offers the perfect window into the cell’s DNA repair machinery. By studying that disease she has found answers to much broader questions.
Agata’s passion for science began as a child in her native Poland, when she became smitten with a water machine. A huge apparatus in her grandmother’s chemistry laboratory, it distilled and purified the water needed for experiments. When Agata visited the lab, her grandmother would assign her to work the part that regulated the water’s flow. “I’m sure it didn’t matter how fast or slowly it flowed,” she laughs, “but I loved that machine. For me, it was a special honor—and my first real experiment.”
Agata, who is associate professor and head of the Laboratory of Genome Maintenance, comes from a family of scientists: Two of her grandparents were chemists, her mother was an immunologist, and her father is a physician. So one might safely assume it’s in her DNA—the mysteries of which she’s devoted herself to illuminating. “Early in my career I decided I wanted to look at DNA repair during replication,” says Agata. At Rockefeller, she has been able to establish a lab that studies this process through a unique lens: the rare genetic disorder called Fanconi anemia.
“In a different place I would be doing very different research. Rockefeller believes in us and empowers us to do the very finest work we can.”
Ancient problem, fresh approach
DNA is subject to constant assaults from UV radiation and toxins, and to mistakes that happen during DNA replication. Together, these assaults can introduce thousands of errors, which if not fixed—or if fixed incorrectly—can result in cancer and other problems.
Agata received her M.D. from Weill Cornell Medicine and her Ph.D. from Rockefeller. As a postdoc in the lab of Harvard molecular biologist Stephen Elledge she identified the gene FANC1 and showed that it is part of a process called DNA interstrand crosslink repair, which removes inappropriate attachments between DNA strands. Mutations in FANC1 result in Fanconi anemia, which brings developmental abnormalities, bone marrow failure, and a predisposition to a variety of cancers.
Since joining the Rockefeller faculty in 2009, she has sought to reveal the mechanisms of interstrand crosslink repair and to understand how dysfunction in this repair leads to disease.
Agata partnered with clinical geneticist Arleen Auerbach, who in 1982 had founded Rockefeller’s International Fanconi Anemia Registry (IFAR). The registry provides researchers who study Fanconi anemia access to a large number of patients with the disease. “IFAR now includes information and cell lines from more than 1,000 families and has helped my lab identify new genes involved in Fanconi anemia,” she says. “This is a wonderful point of entry to understand the mechanism and function of interstrand crosslink repair, and the registry has been an incredible resource.”
Agata’s current projects include studying the pathogenesis of a type of chronic kidney failure that arises from mutations in the FAN1 gene—another component of the interstrand crosslink repair pathway. She is also starting to catalog and assess the genomic changes in head and neck cancers in patients with Fanconi anemia. “We’d like to know what drives these cancers to develop and hope that the information we gain will give us new ways to treat them, or even identify them earlier, before they become very difficult to treat.”
Independence with support
Upon entering The Rockefeller University for the first time, Agata recalls she found “an oasis of science. I had a very profound, visceral feeling about it the moment I stepped onto the grounds.”
Not only did she discover a haven on a lush campus in the middle of the city, but she found a community of like-minded, high-achieving scientists. Expectations are high, she says, but the tools and support needed to meet those expectations are readily available. “As a scientist, you can be doing whatever you want to be doing—nobody is going to tell you what to study,” she says. “You’re really your own department; you have the freedom to follow your instincts and be creative. I love that and I thrive here.”