sign in sign up
<<
Home , Aaron Ciechanover, Avram Hershko, Irwin Rose

A conversation with

Ushma S. Neill

J Clin Invest. 2013;123(10):4093-4094. https://doi.org/10.1172/JCI71859.

Conversations with Giants in Medicine

For decades, the attention of the scientific community was focused on the central dogma of — the decoding of the genetic information embedded in DNA. Little research was dedicated to how proteins are degraded and removed from cells. Enter onto the scene a young graduate student, Aaron Ciechanover, who with his mentor , uncovered the complex and elegant proteolytic system. For his discovery, Ciechanover (Figure 1) shared in the 2004 in with Hershko and . The complete interview, with more stories about being a member of the Pontifical Academy of , the magic of “A-ha” moments, and the conflict between religion and Darwinism, can be seen on the JCI website, http://www.jci.org/kiosk/cgm. JCI: What was your childhood like? Ciechanover: I was born in in 1947, the year Israel became independent, to parents that had emigrated as children from Poland, escaping the rising anti-Semitism there. I grew up in a modest Jewish conservative home. My mother was an English teacher and my father a lawyer. I remember that our home was cluttered with books. We had wall-to-wall, floor-to-ceiling libraries filled with Jewish and law books, but not so many on , as I was the only one interested in science. My parents taught me to read and write early on. It was a scholarly […]

Find the latest version: https://jci.me/71859/pdf Conversations with giants in medicine A conversation with Aaron Ciechanover

For decades, the attention of the scien- my PhD with him. tific community was focused on the central JCI: How did you come across the idea to dogma of biology — the decoding of the study protein degradation? genetic information embedded in DNA. Lit- Ciechanover: Avram had started to work tle research was dedicated to how proteins are on the subject when he was a fellow at UCSF. degraded and removed from cells. Enter onto He had come across earlier — apparently the scene a young graduate student, Aaron thermodynamically paradoxical data — that Ciechanover, who with his mentor Avram protein degradation in both bacteria and Hershko, uncovered the complex and elegant mammalian cells require metabolic energy. ubiquitin proteolytic system. For his discov- Our dietary proteins provide us with energy, ery, Ciechanover (Figure 1) shared in the so it did not make sense to invest energy to 2004 with Hershko degrade them to their low-energy amino and Irwin Rose. The complete interview, with acids building blocks. Yet, energy is required more stories about being a member of the for proteolysis via the lysosome that was dis- Pontifical Academy of Sciences, the magic of covered by , as the mainte- “A-ha” moments, and the conflict between nance of its low acidic milieu requires pump- religion and Darwinism, can be seen on the ing of hydrogen ions. There were, however, JCI website, http://www.jci.org/kiosk/cgm. signs in the literature that it was not the JCI: What was your childhood like? lysosome that degrades most of intracellular Ciechanover: I was born in Israel in 1947, proteins. We hung on those findings and the year Israel became independent, to par- glued them together, initiating a search for a ents that had emigrated as children from non-lysosomal proteolytic system. Poland, escaping the rising anti-Semitism We started by establishing a cell-free there. I grew up in a modest Jewish conser- Figure 1 system from reticulocytes that degrades a vative home. My mother was an English Aaron Ciechanover on May 9, 2013. Image model protein. Shortly after, we realized we credit: Alena Soboleva. teacher and my father a lawyer. had a novel finding — the activity we discov- I remember that our home was cluttered ered was not resolved as expected, as a single with books. We had wall-to-wall, floor-to- plexity of the human body and disease protease, but rather as two complementing ceiling libraries filled with Jewish and law mechanisms. inter-dependent activities. At that point in books, but not so many on science, as I was I joined a program called the “Academic the summer of 1977, less than a year after the only one interested in science. My parents Reserve” where the Israeli military postpones I started my studies, Avram went on sab- taught me to read and write early on. It was a the mandatory national service for students batical to Philadelphia to work with Irwin scholarly environment, but very free. I have a who study professions that are also in need [Ernie] Rose, and I stayed behind in Israel. brother who is 14 years older than I am, and I for the Army, as medicine and engineering JCI: How did you hit on using red cells was lucky to have this age difference, because for example. The first years at the Hebrew extracts? when my parents died during my childhood, University in were exciting because Ciechanover: The reticulocyte is a great cell, he and my aunt kind of adopted me. we studied basic sciences such as biochemis- because it doesn’t have lysosomes; along its JCI: What kindled your interest in science? try, microbiology, and pathology. differentiation to the mature red blood cell, Ciechanover: I cannot pinpoint it, by But, when we approached the clinic, I it extensively degrades all its machineries and maybe it was the close vicinity to . I started to feel restless — it was not what I proteins, leaving behind mostly hemoglobin. used to walk on the slopes of the Carmel wanted to do — and I decided to take a year The problem was that hemoglobin com- Mountain just behind our home, collecting off and carry out research in biochemistry; prises ~85% of all the cellular proteins, and and drawing flowers, plants, lizards, skel- I fell in love with this discipline. I then com- it was difficult getting rid of it. One of our etons — so it was an interest in what I would pleted my medical studies and my military two complementing activities was resolving call today ‘taxonomic’ biology. When I was service as a combat physician, including along with hemoglobin, but we could not 11-years-old, my brother went abroad and serving in the 1973 war. After being dis- isolate the culprit whatever we did. As a last I asked him to bring me a microscope — I charged, I landed safely in biochemistry. resort, and while Avram was away, along with still have it. My first tiny, small microscope! JCI: It was after this that you first came to a colleague of mine, Michael Fry, we decided I started to do experiments: peeling onions Avram Hershko’s laboratory? to literally boil the “red” extract. The hemo- and putting the thin layers under the micro- Ciechanover: Medical students have to globin precipitated like mud and the yellow- scope to see the cells, immersing them in submit a small research thesis in order to ish supernatant had all the activity. While pure and salted water to expand and shrink graduate. This I did with Avram Hershko, we could not believe it was a protein, it was the cells. I remember piercing myself with a who had just returned from his postdoc- sensitive to proteases, had a high molecular needle and smearing blood on a cover glass. toral training as a young assistant professor. weight, and was precipitable with ammoni- JCI: What led you to medical school? We kept our ties during my military combat um sulfate. The two findings — the two com- Ciechanover: I was interested in the com- physician service after which I decided to do plementing activities and the heat resistance

The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 10 October 2013 4093 conversations with giants in medicine of one of them — were critically important as important experience, but then, I gradually 35 years later? they set our future research direction. These slid back to work on ubiquitin. Ciechanover: More than ever! We haven’t embarrassingly simple experiments were JCI: Meaning that during that time you even begun to understand the complexity published in BBRC after they were rejected were also interacting with Alexander Var- of the system. It has almost 2,000 compo- from JBC, teaching us an important lesson, shavsky, who drew you back into ubiquitin nents, approximately 7% of the human particularly these days — it does not matter research. genome. The ubiquitin system plays a where you publish but what you publish. Ciechanover: Alex had discovered in major role in clearing defective/misfolded JCI: Rose provided crucial input, given the literature a temperature-sensitive cell proteins. Besides quality control, it removes that he was coming at the problem from a cycle arrest mutant in which ubiquitinated in a programmed manner important cel- different direction. histone H2A disappeared at the high tem- lular proteins like cell cycle regulators and Ciechanover: During the summer of ‘79, perature. We discussed and thought either transcription factors. Importantly, there are on another visit to the Fox Chase Cancer the cells lost their ability to ubiquitinate the drugs already on the market to treat aberra- Center, Ernie helped us to solve an impor- histone or gained the ability to rapidly deu- tions in the system and now more diseases — tant problem. Beforehand we had purified biquitinate it. It made more sense that they inflammatory disorders, neurodegenerative the active heat-stable polypeptide and real- lost their ability to ubiquitinate, as muta- diseases and malignancies — are being tied ized that when incubated in the presence of tions typically result in a loss of function. to defects in the system. ATP and the other active fraction, it gener- Along with Daniel Finley, a graduate student JCI: You’ve said you did your science ated high molecular weight complex with in Alex’s laboratory, we ended up discovering because of scientific curiosity, not to win some other protein(s). We thought that the a mutation in E1 — the ubiquitin-activating prizes. But surely, sharing in the Nobel complex could result from a gentle associa- enzyme, the first enzyme in the ubiquitina- Prize with Hershko and Rose must have tion — for example, a cryptic protease that tion cascade. Needless to say, the cells were been fairly sweet. is activated by our protein. With Ernie’s defective also in degradation of short-lived Ciechanover: You celebrate for one day, advice, we found that ATP helps to catalyze a proteins. We were lucky, because if it had and then you celebrate the second day, stable peptide bond between our protein and been a mutation in the histone E3, it would and the third day you have to decide what endogenous substrates in the crude extract, have taken a long time to discover it. Since it you are going to do with yourself. I decid- and hypothesized that this conjugation sig- was a cell cycle arrest mutant, we speculated ed to do two things: first, to continue my nals the tagged proteins for degradation. We that the ubiquitin system is involved also research; being in the laboratory is so excit- called our first purified protein APF-1 (ATP- in cell cycle regulation, which later turned ing now, with smart students and fellows, dependent proteolysis Factor-1). Other peo- out to be correct. The description of the E1 and sophisticated technologies. Second, to ple at Fox Chase highlighted to us a protein mutation was another corroboration of our leverage my ‘status’ to highlight two major with a similar molecular weight — ubiquitin earlier findings that ubiquitination signals issues. One is education of children in Isra- — that is conjugated to histone H2A in an proteins for degradation. el and worldwide. I talk to them at eye level isopeptide bond. The similarity to APF-1 I went on to study the requirement for and they see, wow — it is possible to make a was striking, and along with Keith Wilkin- tRNA in the proteolytic process, which I major achievement and still remain a regu- son and Art Haas at Fox Chase, we found discovered when I was still with Avram, but lar human being. We need children falling that APF-1 was indeed ubiquitin. This was never pursued. This turned out later to be in love with science at an early age. an important discovery, as not only it did part of the N-end rule, discovered and stud- The recognition also enabled me to trace unravel the nature of the chemical bond ied independently by Alex. Basically, in the my Jewish heritage. I try to build close rela- between APF-1 and its target substrate, but second half of my post-doctoral fellowship, tions with Jewish communities, mostly it also explained the mechanism of action of I became a ‘freelancer’ in Harvey’s laborato- small and remote ones. For example, there ATP, solving the energy requirement mys- ry. He did not know much about ubiquitin, is a tiny Jewish community in Greece left tery, and enabled the discovery of the con- but was gracious to learn it and help me. I after the extermination during the holo- jugating machinery that is made of three owe a lot to the independence that Harvey caust, or a tiny one in Paraguay made enzymes: E1, E2, and E3, that act in concert. gave me and to the openness I enjoyed in mostly of holocaust survivors. I speak in JCI: What motivated you to do your post- his laboratory. I remember fondly his advice different community activities — sermons doc with at MIT? when I hesitated about returning to Israel. in synagogues, for example — and it is fas- Ciechanover: Following graduation, He was all for it, where he knew my family cinating, as I feel I blow wind in their sails. I though I could stay as a faculty member, I will be most comfortable. He argued that feel an amazing sense of belonging. wanted to become independent. I wrote to even under less favorable conditions it is JCI: If you were not a scientist, what do Harvey who worked on the cleavage of the mostly the scientist’s quality and drive that you think you would have done? Poliovirus polyprotein. would be detrimental to his/her success. Ciechanover: The natural track would have Arriving at the laboratory, Harvey suggest- JCI: You decided to go back to the same taken me to surgery, and I believe to cardiac ed I could work on receptor-mediated endo­ institute as Hershko in Israel. or neurosurgery. There is something mystical cytosis. This was good advice: coming from Ciechanover: To the same institute, yes, about these two organs where emotion and pure biochemistry, I not only delved into a but I was completely independent. I brought reason reside. But the fact that the discovery new field — that of cell biology and the prob- my own projects and started an indepen- of the ubiquitin system led to the unraveling lem of routing of proteins in cells — but, along dent career, completely away from Avram, of related diseases and development of drugs with Alan Schwartz and Alice Dautry-Varsat, though being close and having the ability to is kind of a cycle closure for me. we discovered the cycle of the transferrin discuss problems clearly helped. receptor and iron delivery into cells. It was an JCI: Does ubiquitin still motivate you, Ushma S. Neill

4094 The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 10 October 2013