Angelika Amon's research into the cell cycle and aneuploidy caught our attention. Curious to know more, BioTechniques contacted her to find out about the ambition, character, and motivation that led to her success.More to the Story
What do you consider to be your most significant scientific contribution?
When I completed graduate school, it was commonly believed that the only thing needed for cells to exit mitosis was inactivation of cyclin-dependent kinases. At the final stage of the cell cycle, after cells have finished segregating their chromosomes but before they enter G1, there are a lot of intricate regulations controlling that exit from mitosis. Lee Hartwell had previously performed a cell-division cycle screen identifying many mutants defective in this process. This suggested to me that there was a lot more to the story than simply degrading cyclins, so we decided to explore this further. One of my lab's most important contributions was defining the pathways and mechanisms governing exit from mitosis using budding yeast as a model system.
During the course of your research, what has been your biggest surprise?
My favorite protein in the world is a phosphatase called Cdc14, a cell cycle phosphatase that triggers the exit from mitosis and regulates important aspects of chromosome segregation. In 1998, we discovered that this phosphatase localizes in the nucleolus. At that time, the nucleolus was probably the most boring place for a protein, and I refused to believe that my favorite protein was stuck in this site of rRNA synthesis, processing, and ribosome assembly. We did so many experiments to try to disprove it, but finally we published it. Within a year of our paper showing the importance of Cdc14 and its localization in the nucleolus, a flurry of papers came out showing that other important cell cycle regulators and checkpoint proteins were also in the nucleolus. It was almost as if everyone knew their protein was in the nucleolus, but was too embarrassed to tell the world. Once Cdc14 broke the ice, the others published it too, which was a big surprise that led to a whole new paradigm of nucleolar sequestration for cell cycle proteins.
What are you working on now?
We continue to work on mitosis and I have a small effort in meiosis as well, but our main focus now is using yeast and mice to study aneuploidy. When applying for NIH grants, I always write that studying chromosome segregation is important because when it goes wrong, cells become aneuploid, a condition associated with cancer. But it always bothered me that we really didn't understand what it meant for a cell to have the wrong number of chromosomes. How does getting an extra chromosome or losing a chromosome lead to cells proliferating and becoming cancerous? I decided I wanted to tackle the question of the physiological response to changing the gene dosage of hundreds if not thousands of genes at the same time.
It has been very complicated to parse out the contributions of changing the copy numbers of individual genes versus system-wide changes and which general cell pathways are affected by these large-scale genomic changes. But we have made some significant contributions in defining what it means for cells and organisms to be aneuploid and the impact of this condition on many aspects of cell physiology. That's something we are very interested in and excited about at the moment.
My newest passion, though, is looking into mitochondria. I have always been fascinated by mitochondria because at some point they were an invasive species. I have always wondered how the eukaryotic nucleus learned to talk to the mitochondria and vice versa. How did they establish communication between species from different kingdoms? What kind of language did they develop? Did the nucleus learn French? Did the mitochondria learn English? Or are they so different that they had to invent something new and primitive? We are trying to understand how the mitochondria communicate their needs across two membranes and how this communication evolved.
How are you approaching that question?
First, we are trying to stress the mitochondria in various ways and then look at the responses in the nucleus– the gene expression changes that occur in response to various mitochondrial perturbations. Then we will use genetic approaches to find mutants that can't mount this response to study the mechanisms and consequences for the cell.
I believe it's important to study biological questions in the simplest organism possible. Yeast lends itself well to these very broad genetic questions, so our initial efforts are in yeast. But there are so many mitochondrial proteins not conserved between species, indicating that these interactions are still evolving even after the various eukaryotic phyla have been formed. So in this particular instance, it might very well be worth looking at it in many different species and many different systems.