An animated movie based on the work of IDI Senior Investigator Tom Kirchhausen recently took first prize at the cell biology community’s version of the Academy Awards. The video, which illustrates a fundamental process by which cells take up nutrients and other materials from their surroundings, was honored by the American Society of Cell Biology at its December meeting. Since 2005, the ASCB has run the annual Celldance competition, a contest to select top images that are both scientifically important and visually engaging.

The choreography and animation is the work of Janet Iwasa, Lecturer in Molecular Visualization in the Cell Biology Department at Harvard Medical School. Iwasa worked with Kirchhausen to produce the 2 minute animation, which embodies years of work by the Kirchhausen lab on the structure and dynamics of the clathrin protein. Clathrin is the main component of the machinery responsible for pulling receptors and their cargo from the cell surface inside the cell. 

Set to Rimsky-Korsakov’s Flight of the Bumblebee, the animation starts with the iron-carrying transferrin receptor buzzing around on the outside surface of a cell. Soon, the receptor is enveloped and dragged inside by a swarm of clathrin triskelions that assemble into a soccer ball-shaped cage. The clathrin coat is released when accessory proteins fly in to dissociate the triskelions and disperse the cage structure.

The sequence is no flight of fancy. Each frame is backed up by hard scientific data, much of it produced in the Kirchhausen lab. “The idea was to restrict ourselves to data supported by 3D information from crystal structures and cryo EM structures, combined with information obtained by live cell imaging. The long term goal is to generate what we refer to as molecular movies, a term to denote efforts to describe molecular interactions reflecting real interactions in time and space,” Kirchhausen said.

The prize-winning movie is a sequel to a 2000 animation from the lab that has worked its way into textbooks of cell biology. That work was based on Kirchhausen pioneering work on the structure of the clathrin protein and the way multiple clathrin molecules pack together to form the clathrin coat. With recent advances in understanding of coat structure and dynamics, it was time to update that version, Kirchhausen said. In particular, high-resolution structures of some of the other proteins involved, garnered from X-ray crystallography studies, has brought endocytosis into sharper focus. Also, new imaging techniques that let the researchers tag different proteins with fluorescent colors and watch endocytosis in live cells has given new insights as to the timing of coat formation.

With all of the latest data incorporated, the new animation serves several purposes. One is to communicate a complicated series of biological interactions in a way that is immediately clear to researchers, students and the general public. “The movie facilitates understanding of a really complicated phenomenon,” Kirchhausen explains. “There are so many components of the coat. It is not just sequential events, but a lot of parallel interactions that are very difficult to explain with words or still pictures.”

Secondly, for the researchers, putting the movie together frame by frame forced them to take a hard look at their own data, and to realize what parts were clear and which parts still need work. “It’s like making a jigsaw puzzle, where you have to understand how to put the pieces together,” Kirchhausen says. “That forces us to better understand where there are gaps and things we don’t understand.”

Iwasa agrees, saying that the process of creating the animations “requires scientists to think hard about what their models are. The process can be very informative for the researchers.”

Despite the large amount of data that supports such animations, it is important to remember that they are only estimations of how researchers think things work. “This is not a picture of reality,” Iwasa says. “It’s a thought model.” That means that not all researchers will necessarily agree with the details of the movie, but Iwasa hopes that the animation at least provide a way for people to compare their models, and point out specific areas where they disagree.

Moving forward, Kirchhausen sees more sequels in his future, as new data allows further refinement. For her part, Iwasa is working on developing new animation tools to help researchers use visualization to both communicate their research, and to advance their own understanding of the beautiful processes they study.