Life unfolding

Life unfolding

Graduate student Marlis Denk-Lobnig investigates the biological forces that shape developing tissue to dictate form and function.

Raleigh McElvery
March 22, 2019

A few hours after fertilization, the fruit fly embryo is just a hollow sphere, slightly oblong in shape, until a band of cells on its surface furrows inward to form a new layer. This folding process takes only 15 minutes, but it’s critical for determining where the cells will go and what roles they will eventually play. In humans, errors in tissue folding can result in diseases like spina bifida, where the spine never fully closes.

Fourth-year graduate student Marlis Denk-Lobnig watches this gastrulation process occurring in fly embryos in real time, tagging molecules with fluorescent proteins to probe the forces that eventually shape a fully-formed organism. Every day, she gets to witness new life unfold — literally.

Denk-Lobnig spends most of her time with her eye to a microscope or generating genetic crosses in the “fly room” where she keeps her stocks — rows of tubes containing light brown insect food that emits an unmistakable odor, despite being corked with cotton swabs. Inside each neatly labeled container, scores of tiny flies mill around as they lay eggs and feast.

Given that her mother trained in chemistry and her father in physics, “it didn’t take much creativity to get into science early on.” Denk-Lobnig enjoyed physics throughout high school, but also maintained a keen interest in biology, which became more pronounced after she was diagnosed with an autoimmune disease affecting her thyroid and adrenal glands.

“In some ways, the question of how your own body works is the most tangible question to ask,” she says. “It’s fascinating to connect everyday experiences with mechanisms, and studying biology and medicine seemed like a powerful way to have a direct impact on life.”

She majored in molecular medicine at Georg August University in Göttingen, Germany, located several hours from her childhood home in Heidelberg. Inspired by a summer internship with MIT Biology alum and Rockefeller professor Cori Bargmann PhD ’87, Denk-Lobnig centered her undergraduate thesis on the role glial cells play in disease.

She graduated after only three years, the typical duration in Germany, and spent the next several months traveling and applying to graduate schools. She also visited Nepal, where she taught visual and performing arts — and a bit of gymnastics — at a local boarding school.

When she began at MIT in 2015, Denk-Lobnig took the opportunity to blend her expertise in biology with a renewed enthusiasm for physics. Although she is a full-fledged member of the Department of Biology, she is simultaneously enrolled in the interdepartmental Biophysics Certificate Program.

“Not many people know that MIT has a thriving biophysics community,” she says. “It’s a mix of mechanical engineers, chemists, biologists, and physicists. There are specific course requirements, and we go on retreats and participate in seminars to share our research and discuss collaborations.”

As a member of Adam Martin’s lab, Denk-Lobnig studies the cellular forces that shape tissue form and function. Martin is also affiliated with the certificate program, and was one of the faculty members who initially interviewed Denk-Lobnig for the graduate program.

“Biophysics is all about finding elegant explanations for everyday phenomena, and I really enjoy thinking about physical principles and how they apply to biological problems,” Denk-Lobnig says. “The methods we use in the Martin lab are also incredibly visual. You can literally see a fruit fly embryo fold, and watch as a sheet of cells furrows inside the embryo to form a second layer, which is important for development. It’s both informative and aesthetically pleasing.”

Denk-Lobnig began by focusing on a single molecule called Cumberland-GAP (C-GAP), which regulates one of the many proteins in charge of tissue folding: myosin. Myosin is responsible for muscle contraction, among other duties. With its characteristic forked shape — two “heads” protruding from string-like “tail” domain — myosin can appear to walk along the cell’s scaffolding, sometimes transporting cargo. Denk-Lobnig, though, is most interested in myosin’s ability to pull on developing tissue and create a fold.

Right before graduating, one of Denk-Lobnig’s former labmates noticed that depleting C-GAP seemed to alter the concentration (or “gradient”) of myosin across the tissue. Since this finding pertained to the very regulator she was studying, it piqued Denk-Lobnig’s interest. She wanted to know how molecules like C-GAP might influence myosin and impact folding, and her scope widened from the molecular level to include the entire tissue.

It’s unlikely, she says, that myosin is pulling with equal force across the tissue — “that wouldn’t constrict the sheet of cells very efficiently.” Instead, there’s probably more myosin in middle and less towards the edges, which contracts the cells in the middle of the sheet to a greater degree and creates the curvature that forms the crease of the fold. In the fruit fly, gastrulation occurs just three hours after the eggs are laid. Because the folding happens at the surface of the embryo, there’s no need for dissection to witness the entire event through a microscope.

Denk-Lobnig has begun exploring other regulators besides C-GAP to analyze their effects on the myosin gradient and cell curvature. She was one of the first members of the lab to introduce CRISPR-Cas9 into their testing protocol, and is currently the only one experimenting with optogenetic techniques. She also regularly participates in the lab book club, which features classics like The Bell Jar and One Hundred Years of Solitude.

Outside of lab, Denk-Lobnig serves as the president of MIT’s women’s club gymnastics team, volunteers to help run weekly Gymnastics Special Olympics events, and sings in a graduate student choir. She is also a member of the department’s peer support program, bioREFs.

Long-term, she plans to stay in academia and delve further into physics-based methods, like modeling and coding. If she could find a project that’s just as visual as her current work in the Martin lab, “that would definitely be a plus.”

Posted 3.21.19