Aaron Ciechanover (left) and Roy Arama (right, a junior associate in the Steller lab) found that they share a passion for toy trains. photo by Eli Arama

NS: Why did you decide to spend your sabbatical in the Steller lab?

AC: We have been collaborating for three years on the role of the ubiquitin system in apoptosis, and we published a paper together with Hyung Don Ryoo and Hermann Steller in Nature Cell Biology. We were interested in a collection of enzymes called IAPs (Inhibitors of Apoptosis). These are ubiquitin ligases positioned in the center of the very downstream part of the apoptotic pathway and these enzymes target caspases (the executioners of apoptosis) for degradation by the ubiquitin system. Upstream of IAPs there is a group of IAP-binding proteins that were discovered by Hermann Steller in the fruit fly which are called reaper, hid, and grim and they inhibit IAPs. We were wondering, “how do they inhibit them?” We showed that they accelerate their ubiquitination, so the ubiquitin ligase itself is committing suicide via the ubiquitin system. So we have here yet another layer of regulation.

When looking for a place for a sabbatical I thought: I am not a fly geneticist, I am a biochemist and cell biologist – but it would be nice to at least understand the language of Drosophila genetics. It turned out to be a very enjoyable experience and now I feel that I speak the fly language a little bit.

I hope to come for a second sabbatical, maybe I will send students here. Our dialogue will certainly accelerate.

Aaron Ciechanover, a co-recipient of this year’s Nobel Prize in Chemistry, spent his sabbatical leave here at Rockefeller in the lab of Hermann Steller. photo by Eli Arama

NS: Did you end up doing some hands-on fly genetics?

AC: I did not, I did some experiments here on a concept that we had, I learned lots of techniques from Eli Arama and Hyung Don. It was Hermann who introduced me to the world of apoptosis. The entire idea of linking apoptosis to the ubiquitin system came from Hermann and now we are heavily working on it in my lab. My stay here was kind of an introduction to apoptosis techniques for me and now I hope to adopt them more extensively in my own research.

NS: It has been quite a long way from the first fractionation experiments you made in the seventies to this detailed understanding of the ubiquitin system at the molecular level.

AC: Well, it was a long way, but we were not the only ones. There were a number of labs around the world that paved this road and expanded it. Apoptosis is just one of the many areas where the ubiquitin system plays an important role. Understanding control of apoptosis is important for cancer treatment, because one of the major aberrations in cancer is the aberrant execution of apoptosis. Many scientists and drug companies would like to understand how cancer cells evade apoptosis. And obviously we want to look at it from the ubiquitin point of view. This is not only interesting basic research but also an important field of applied medicine, and therefore we are very excited about it. We still don’t understand the role of the ubiquitin system in the regulation of apoptosis, we only see the tip of the iceberg. Solving the interaction of the ubiquitin system and apoptotic pathways on a molecular level will probably yield important practical results.

NS: When we look back, it appears that the idea of non-lysosomal protein degradation was quite radical at the time.

AC: Yes, it was. I should give credit to my mentor, Avram Hershko. I was his graduate student at the time and the idea to look into this was his. But real experiments were done with these hands [laughing]. We were joined by other people in the lab, like Hannah Heller (she contributed a lot), and of course Irwin Rose, our co-recipient. All the understanding of chemistry and enzymology was done in his lab. The breakthrough came in 1979 when we really understood the chain of reactions. Irwin, as an enzymologist, really opened the door for us to understand the underlying catalytic mechanism. We were lucky to make the right choice. People at the time were busy trying to understand how DNA is being transcribed and translated. People didn’t think that protein degradation was important. They viewed it as a scavenger mechanism, as an end-process. Nobody thought of specificity of protein degradation at that time. We were lucky, because typically a small faraway lab from the Middle East would not have a chance; the American sharks quickly take over as soon as they smell an important thing. Luckily the sharks were sleeping. Actually for seven successive years nobody really cared what we were doing. People thought that it was all an artifact.

NS: One last question. Did you have time to explore the city, what did you like here?

AC: This was not my first time in New York. I enjoy the theaters, restaurants and such, but this time around I spent quite a lot of time in the lab. Actually people kept making fun of me, because I was always first in the lab in the morning. I had a great time here, met new friends. I will return to Rockefeller like home every time I fly to the US.