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Nominata goes to Mingjian Du for advances in innate immunity

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Growing up in a small village in northwest China, Mingjian Du became fascinated with life science while helping on his parents’ family farm and later while studying biology in high school.

My parents have the best scientific spirits, which they showed in improving crop yields and quality. My mom told me that science is all around us, said the recipient of the 2019 Nominata Award, the highest honor that UT Southwestern bestows on a student in the Graduate School of Biomedical Sciences. Then my high school teacher got me interested in understanding biological activities, encouraged me to pursue my studies, and gave me the confidence to try for college.

Mr. Du excelled academically, placing second out of 160,000 students on the national college entrance exam in his province. He was accepted to Tsinghua University, described as the MIT of China. There he trained in several laboratories, including one run by a world-renowned structural biologist.

In China, the only way for children from the poor countryside to change their destinies and improve their futures is to get an education, especially college. I’m one of them, and I studied very hard to get decent grades, he said.

Mr. Du is a fifth-year graduate student in the UT Southwestern laboratory of Dr. Zhijian “James” Chen – Director of the Center for Inflammation Research, Professor of Molecular Biology, and a Howard Hughes Medical Institute Investigator. Mr. Du recently presented the Nominata Lecture, describing his work on innate immunity to an audience of faculty members and fellow graduate students. Traditionally, that talk is the final one in the University Lecture Series attended by the University’s top researchers.

It’s such an incredible honor to receive this award and to share my research in a University lecture, although it did make me nervous to think of talking to so many top scientists, he said, adding that he chose UT Southwestern for graduate school because of its international reputation.

My mentor, Dr. Chen, is one of the best scientists in the whole world to study cellular signaling using traditional biochemical approaches, and he made several fundamental discoveries on innate immune signaling pathways. Mr. Du said. He prefers for us to work independently in the lab, but provides tremendous help and support if we encounter difficulties. He is very busy, but very nice and patient, willing to spend time with students. I admire his commitment and persistence in science and he is my role model for doing research.

Mr. Du’s thesis work focuses on the activation of innate immune signaling by DNA-induced liquid phase condensation of cyclic GMP-AMP synthase (cGAS), the cellular sensor of DNA discovered in 2012 in the lab of Dr. Chen, who became UT Southwestern’s newest Breakthrough Prize winner based on that advance.

When he arrived for a graduate school rotation in the Chen lab, Mr. Du was given the tedious but important research needed to characterize single- and double-stranded DNA of different lengths, DNA/RNA hybrids, as well as DNA from different species and organelles within the cell to determine those to which the DNA sensor cGAS reacted most strongly.

The experiments required careful planning and long hours in the lab. By working through the winter holiday, he moved the project to an advanced stage before leaving to complete his other rotations, then returned to continue the painstaking work. He observed these oddities about cGAS:

  • Long DNA activates cGAS more efficiently than short DNA.
  • cGAS activity increases acutely when it surpasses a certain concentration.
  • cGAS forms foci (which look like droplets under the microscope) with DNA in the cytoplasm.

His observations caused him to suspect that cGAS might be undergoing protein liquid-liquid phase separation, a physical chemistry process he had encountered during a rotation in the laboratory of Dr. Michael Rosen, Chair of Biophysics and a pioneer in showing that liquid-liquid phase separation is vital for a variety of biological processes.

Next, Mr. Du conducted experiments that confirmed the activation of cGAS via DNA-induced liquid phase separation. He also identified a switch-like threshold effect that helped explain how cGAS can detect and respond to infection from pathogenic DNA while avoiding reacting to low amounts of self-DNA in the cytoplasm, said Dr. Chen, who is also a member of the Center for the Genetics of Host Defense.

Dr. Zhijian “James” Chen
Dr. Zhijian “James” Chen

As a result, Mr. Du became lead author on a two-author study with Dr. Chen published in Science last year that finds cGAS forms droplets (foci) that act as tiny bioreactors creating molecules to stimulate innate immunity – the body’s first response to infection. “I should stress that Mingjian single-handedly conceived and executed all the experiments that led to the exciting discoveries reported in his Science paper,” Dr. Chen added.

Dr. Chen said he expects Mr. Du’s findings to greatly facilitate the design and development of cGAS inhibitors, therapeutics that have the potential to treat autoimmune diseases such as lupus.

It is very likely that several other proteins involved in innate immunity and inflammation also have similar liquid phase separation behavior and I believe his paper will have a great impact in the immunology field, Dr. Chen said. In summary, Mingjian is a highly talented, extremely driven student who has the potential to become a next-generation scientific leader.

Mr. Du plans to return for a sixth year. After graduate school, he intends to pursue postdoctoral work in neuroscience.

I’m fascinated and obsessed with fundamental questions such as how memory is initiated, consolidated, and recalled. Additionally, a role of quantum physics in consciousness has been implied, and I’m also very interested in studying that possibility, he added.

He hopes his parents, who still live in China, may be able to visit when he graduates and said that they support him and are proud of his accomplishments, though it is hard for them to understand his work. Mr. Du visits them every year or two.

Sometimes tears come from my mom and she says that she misses me on video chat, but this gives me the momentum to work hard, he said.

In addition to Mr. Du’s honor, Dr. Bishakha Mona of the Genetics, Development, and Disease Graduate Program received a Dean’s Discretionary Award for research excellence and superior ability to communicate her science. Dr. Bishakha, the recipient of the 2019 Ida M. Green Award in April, recently completed her Ph.D. in the laboratory of Dr. Jane Johnson, Professor of Neuroscience.

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