RETROSPECTIVE RETROSPECTIVE Irwin Rose (1926–2015) Judith P. Klinman1 Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, CA 94720 On June 2, 2015, Irwin (Ernie) Rose died Talbot, who recognized that success in bio- quietly in his sleep at age 88, after a long and medical research, cancer included, was ulti- fruitful lifetime of sleuthing for the secrets of mately dependent on the vigor of the life at the molecular level. Truly great scien- underlying basic research. By the time I ar- tists are much more than the sum of their rived at the ICR, a critical mass of fine re- publications and awards. This is especially searchers had been hired to pursue, among true for Ernie who, when informed that he other things, enzyme structure and function. had been awarded the 2004 Nobel Prize in By 1970, the ICR was recognized as a magnet Chemistry, wondered aloud whether he really and training ground for anyone interested needed to go to Sweden to receive this honor. in this burgeoning research area. Although he did attend the ceremonies, and Ernie’s contributions to enzyme mech- appeared to enjoy the process enormously, anisms represent some of his proudest accom- Ernie’s eye was always on the biggest prize of plishments. His approach was straightforward all: understanding how Nature works. and deceptively simple, especially in retro- Ernie was born in Brooklyn, New York but spect: How can one prove that enzymes use relocated with his family to Spokane, Wash- amino acid side chains to perform acid base ington when he was 13 years old. This move chemistry? What is the origin of enzyme ste- Irwin Rose. Reprinted with permission from was dictated by the poor health of one of reochemistry and its relationship to catalysis? University of California, Irvine, CA. his brothers and the recommendation of How do enzymes “reset” themselves after each a high, dry climate to speed his recovery. catalytic turnover? How can cryptic interme- Ernie proceeded to make his way through the diates during enzyme turnover be detected ultimately lead to his Nobel Prize, demon- SpokanepublicschoolsystemandlaterWash- and characterized? The nature of his solutions strating—at the molecular level—how pro- ington State University. Although his family was anything but simple. For example, Ernie’s teins become tagged by ubiquitin as the was unable to provide him much guidance demonstration of a role for an active site base signal for protein arrival at the proteasome regarding a research career in biomedical in proton removal from an organic substrate and subsequent hydrolysis to small peptides. ’ science, this seems not to have deterred him came from the detection of an enzymes abil- This discovery emerged from a fortuitous ’ at all. Ernie s first major research success came ity to retain and transfer an atom of tritium confluence of Ernie’s longstanding interest as a graduate student at the University of Chi- from an initially labeled position in substrate in protein breakdown and a chance meeting cago, where he used the newly available C-14 to a different position in product. His pursuit with Avram Hershko, from Technion Uni- radioisotope to show that deoxycytidine is of enzyme stereochemistry would reveal con- versity, at a Fogerty Conference in Bethesda, produced from its ribonucleoside precursor, sistent patterns that could be directly related Maryland. By 1977 Hershko and his student, cytidine. This important finding immediately both to an evolutionary conservation of active Ciechanover, had uncovered a cellular implicated a new family of enzymes, the site architecture and to a reaction mechanism. factor in protein degradation (initially re- ribonucleotide reductases, in DNA synthe- The detection of productive intermediates ferred to as ATP-dependent proteolysis sis. Given the degree of chemical and struc- during enzyme turnover, an ongoing and dif- factor, APF-1). Annual visits to the ICR tural detail that Ernie would eventually bring ficult challenge, led to one of Ernie’smost each summer by Hershko led to the mech- to his research, it is remarkable that this early elegant contributions: that of positional iso- anism of how APF-1 (renamed ubiquitin) work was initiated before a 3D structure was tope exchange (PIX). PIX, generally applicable undergoes enzymatic activation to become available for either DNA or proteins. The to ATP-dependent reactions, involves labeling ensuing mystery of how enzymes function, of ATP with O-18 in a bridge position and covalently attached to amino side chains a “black box” in the 1950s, was to become a then monitoring the movement of the labeled within the protein targeted for degrada- primary focus of Ernie’s laser sharp intellect. oxygen to a nonbridged position within the tion. The level of chemical intuition and Ernie was my teacher. I first met him in unreacted pool of starting material. PIX intro- sophistication that went into the unravel- 1968, when I joined his laboratory as a post- duced a completely nonperturbative probe for ing of this complicated process is beauti- doctoral researcher. Ernie had become a the reversibility of ATP hydrolysis at enzyme fully captured in a short retrospective by member of the research staff at the Institute active sites, with relevance to many of the most Ernie, published in 2005 (1). of Cancer Research (ICR) in Fox Chase, complex enzyme machines found in biology. Upon my arrival at the ICR, I immediately “ ” ’ Philadelphia, five years earlier, and I was told In the course of his career, Ernie pursued felt the heat of Ernie s fierce style of scientific “how very lucky I was to be able to work many research interests that extended to the with him.” Despite its name, the ICR was control of glycolysis and the role of ATP in Author contributions: J.P.K. wrote the paper. led by a forward-looking leader, Timothy cellular protein breakdown. The latter would 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1512507112 PNAS Early Edition | 1of2 Downloaded by guest on September 25, 2021 interaction. Our early meetings together box” of the origins of enzyme catalysis. In months before Ernie died, he and his son Fred were incredibly stressful for me, in the face later years, after I had moved to the Univer- gave me the gift of traveling from Western of his unrelenting intensity toward science. sity of California, Berkeley, Ernie and I be- Massachusetts to attend my American Society At that time, I was a young mother, trying to came good friends, exchanging visits and for Biochemistry and Molecular Biology balance an uncertain career in science with sending our favorite books back and forth. MildredCohnAwardLectureinBoston.Iam family. In the end, Ernie tolerated the time His passion for science continued unabated, deeply indebted for this last visit, although my constraints imposed by my balancing act, as he would try out thought experiments on deepest debt to Ernie has to be the gift of while insisting on shaping me into a scientist how to solve one of his major and still having one of the great scientific intellects of of whom he could be proud. He must have unsolved interests: the origin of chirality the 20th century as a teacher. seen some promise, because after two years as in living systems. During this period, I also apostdoctoralassociatehegavemetheulti- became friends with his son Bob, who was mate gift of financial support and a free pass a postdoctoral fellow with Tom Alber at 1 Rose IA (2005) Ubiquitin at Fox Chase. Proc Natl Acad Sci USA to pursue my own diggings into the “black the University of California, Berkeley. Just two 102(33):11575–11577. 2of2 | www.pnas.org/cgi/doi/10.1073/pnas.1512507112 Klinman Downloaded by guest on September 25, 2021.