Women in Science: Dr. Anna Dorothea Senft on Keeping an Open Mind?

Meet Anna Dorothea Senft, PhD, MSc, BSc , M.Sc., Ph.D., a postdoctoral researcher in the Macfarlan Lab at NICHD. Dr. Senft is a developmental geneticist who studies how ancient retroviral insertions have shaped our evolution from egg-laying relatives to live-born mammals. “In school, I loved biology, particularly genetics and evolution. I credit my teachers, who were kind, fun, and encouraging, for the experiences that led me to research as a career. I did not know any biologists except my teachers. So I think it was natural that, at first, I wanted to become a biology teacher,” she said.?

Early Years?

Dr. Senft grew up in Mannheim, Germany, about 30 minutes from Heidelberg, a hotspot for research that includes the German Cancer Research Center (DKFZ) and the Ruprecht Karl University of Heidelberg. During high school, she joined an extracurricular group at the DKFZ that engaged students in molecular biology research. There, she was first exposed to developmental gene regulation and became fascinated by molecular biology.?

Initially, Dr. Senft pursued her plan to become a biology teacher and enrolled at Heidelberg University. While still passionate about teaching, she discovered that her favorite subjects, molecular biology and genetics, were not the focus of the teaching curriculum. “When I expressed interest in molecular biology and lab rotations as a teaching student, I simply wasn’t taken as seriously as the science students. I hated that,” shared Dr. Senft. After one semester, she switched her major to biology. “At first, I still planned on becoming a teacher, but after I started my first independent research project, I never went back,” she explained.?

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“Keep an open mind and follow your interests. It was important to me to take a wide range of classes. As an undergraduate, I took a beekeeping course that was run by a molecular geneticist who was interested in evolution. We established a collaboration with an epigenetics lab to pilot honeybees as a model for cancer research and epigenetic therapies,” said Dr. Senft. “I was the only person working with bees in the lab, so I had a chance to work independently early on. My experiments to establish a culture of worker bees in the lab unexpectedly yielded bees that looked intermediate, between a worker bee and a queen bee. My results differed from a report in Science magazine that used a similar protocol to raise worker bees for studying the effects of epigenetic enzymes on honeybee development. That project taught me a lot about science, and I enjoyed working independently. It confirmed to me that I really wanted to pursue research as a career,” she shared.?

Training?

For her master’s degree, Dr. Senft moved to Berlin to study at the Charité University Hospital and Humboldt University, where she majored in molecular medicine. “I stayed in Berlin for three years and became involved in mouse developmental genetics during my thesis at the Max Planck Institute for Molecular Genetics. During that time, I was very productive: I generated valuable genetic tools and mouse lines that gained me authorship on two manuscripts. One of those papers showed how an epigenetic enzyme contributed to the phenotypes of essential developmental genes. I’ve come back to those findings several times during my doctoral and postdoctoral research,” she said.??

Next, Dr. Senft received a fellowship from the Wellcome Trust to move to the University of Oxford for her doctoral studies. “I decided to join the lab because of the mentor, who is a well-known mouse geneticist. I was interested in the genetic and epigenetic mechanisms that govern the earliest cell fate decisions, which establish the mammalian body and germline. Although my mentor had initially planned a different project for me, she allowed me to pursue my own ideas. For the first three years, I put in a lot of work to set up my experiments from scratch. It takes time to become an independent scientist,” said Dr. Senft. Her work paid off. She left Oxford with two first-author publications.?

When she was looking for postdoctoral positions, Dr. Senft read a paper authored by NICHD’s Todd Macfarlan, Ph.D., in Science magazine that suggested that a retroviral insertion may have driven the evolution of an essential regulatory element, which controls an important developmental gene in mammals. She had briefly met Dr. Macfarlan at a conference in Germany and later saw a postdoc opportunity posted on his lab website. “The description listed all my research interests. [Dr. Macfarlan] is a great mentor who fosters independence and confidence. When I joined the lab, I wasn’t given a project but could freely explore. The weekend before I flew to the United States, he asked me to write an NICHD grant for the Human Placenta Project, which I wrote while packing up. My proposal was funded with $55,000, allowing me to buy reagents for experiments and hire a postbaccalaureate trainee in my first year,” she explained.?

Current Research?

The Macfarlan Lab at NICHD works on KRAB zinc finger proteins, believed to have evolved as a defense mechanism against endogenous retroviruses, which are remnants of ancient retroviral infections. However, some of these KRAB zinc finger proteins have been co-opted for other essential functions in the host. Many of these genes are not well studied (see Dr. Senft and Dr. Macfarlan’s review in Nature Reviews Genetics). “I started off by categorizing hundreds of transcription factors and using bioinformatics to identify the ones that were most conserved, expressed in embryos and the placenta, and intolerant to mutations in humans, meaning they are more likely to have an essential role in development,” said Dr. Senft. “I also came across a clinical case in a database, and that helped me select the genes I wanted to knock out in mouse models. The results have been very exciting. The mutation noted in the clinical case has also allowed me to train a clinical fellow, who is now exploring a mouse model for it,” she said.?

Dr. Senft is also exploring the role of KRAB zinc finger proteins in early development. “When co-factors of KRAB zinc finger proteins are knocked out in animal models, the embryos die. Some researchers think it’s because the endogenous retroviruses are reactivating, but this is just based on correlation. We’re currently exploring whether there is a causal relationship between reactivation, developmental defects, and death. The findings could have implications for a variety of health conditions in which endogenous retroviral sequences are abnormally expressed—for example, infertility, cancer, and neurodevelopmental diseases,” said Dr. Senft.?

In the future, Dr. Senft aims to lead her own laboratory. “I have many ideas, some of which date as far back as my early days in Oxford or even my first bee project,” she said. Establishing a new field is exciting, and she is looking forward to continuing her exploration of mammalian development and evolution.?

Read more about Dr. Senft’s research at https://bit.ly/3LhDD6G.