The pathway less taken

Faculty member Alexandra Sobeck is making a name for herself researching a DNA damage response pathway linked to Fanconi anemia.

An assistant professor in the Department of Biochemistry, Molecular Biology and Biophysics, Sobeck has made game-changing discoveries using a unique model system that doesn’t use cells – just extracts from the eggs of the African clawed frog, Xenopus laevis. Although her novel findings have been a tough sell to some in her field, she spends every day reinforcing her discoveries, and she’s doing it with the help and creativity of her lab.

Q: When did you become interested in the Fanconia anemia pathway?

A: I initially wanted to be a veterinarian, but in tenth grade we learned about Mendelian genetics, and that sold me forever on the coolness of genetic inheritance. I started working on FA when I was a graduate student in Germany. I was working on another cancer predisposition pathway called ataxia telangiectasia (AT), and in one of my experiments I found some FA proteins, which got me thinking about other DNA damage repair pathways. After that, my post-doc was focused on FA, and during that time we established the Xenopus model.

Q: What are the advantages of your system over traditional, whole-animal models or cell culture-based systems? How exactly do you harvest the cell extracts?

A: Well, if there is a defect in any of the 16 known FA proteins, you get this human disease, Fanconi anemia. These proteins work more or less exclusively at a particular point of the cell division cycle, and the Xenopus egg extracts are all synchronized at that point. Also, the proteins in an egg are so concentrated compared to a human cell; these two reasons make it much easier to study FA. We harvest the eggs directly from frogs. We inject them with a human pregnancy hormone to get them to lay eggs. Overnight, they will lay thousands of eggs, as much as their own body volume! We use centrifugation to break them open and harvest the extracts.

Q: What has been your best moment as a scientist?

A: My best moment was in my first year here [at the U of M]. We got some data that said that the FA pathway, which everybody thinks is ordered in a series of linear events, doesn’t actually work that way. We found that these two proteins that everyone assumed acted together actually separate when DNA damage occurs and have totally different functions. That was the coolest, looking at that piece of data going ‘Wow, this is exactly the opposite of what the field is thinking.’ It’s hard to work against such a major idea. We’re backing up our findings with additional studies, so I hope we’re convincing more of our colleagues. The FA field, more than any other related field, is really special. You cannot really rely on textbook knowledge; you’ve got to free yourself from everything you’ve learned and go beyond that, go a little crazy! You have to like a challenge.

– Diedre Ribbens