亚瑟• 霍里奇教授自传 (只提供英文版)
I was born in 1951 and grew up in suburban Chicago, exposed to mathematics and science at an early age by my parents. My Dad seemed to vicariously enjoy my interest in science as his career as an engineer had been derailed by World War II. I became a ham radio operator at age ten and spent considerable time building radio equipment and chatting on-the-air. I focused on science and mathematics at Oak Park High School, then matriculated at Brown University in 1969, entering a six-year medical program. There I worked with Michael Czech and John Fain on the mechanism of thermogenesis by brown adipose tissue, enjoying discussion of models and experimentation. I then pursued paediatric medical training at Yale, enjoying application of clinical science to the health of children. During this time, however, I became fascinated with the model of cell transformation by single genes encoded by tumour viruses and, upon completion of residency, went to the Salk Institute in 1978, where I worked on polyoma virus T antigens with Walter Eckhart and Tony Hunter. They taught me molecular biology and biochemistry, and I watched Tony discover tyrosine phosphorylation. At the end of three years in La Jolla, I returned to Yale to receive Medical Genetics and further scientific training with Leon Rosenberg and, during this time, working with the Rosenberg group, was able to clone cDNA encoding the subunit of the hepatic urea cycle enzyme OTC (ornithine transcarbamylase), whose X-linked inherited deficiency leads to lethal ammonia intoxication in affected newborn males. This allowed development of prenatal DNA-based diagnosis. We also pursued OTC biogenesis. OTC is translated in the cytosol, and then enters mitochondria. The cloned cDNA allowed us to observe the sequence of an N-terminal mitochondrial targeting peptide that contained sufficient information to target a protein to mitochondria.
I became an independent investigator in the Genetics Department at Yale in 1984. Here I set out to identify components of the yeast mitochondrion that are required for import of proteins, using human OTC as a model, and this led to our discovery of Hsp60 inside the mitochondrial matrix as a component that mediates de novo folding of imported proteins. That led to work of the next eighteen years, spent analyzing the mechanism by which this double ring component and its homologues in bacteria and elsewhere, the chaperonins, mediate de novo polypeptide chain folding.
In 1990, I became an Investigator of the Howard Hughes Medical Institute, enabling an unlimited degree of experimental freedom in seeking to understand chaperonin mechanism, using biochemical reconstitution with Ulrich Hartl; X-ray crystallography with the late Paul Sigler at Yale to solve structures of the folding machine; EM with Helen Saibil at Birkbeck College, London, to examine structures of the machine, including bound polypeptide; and NMR with Kurt Wüthrich to inspect disordered parts of the system. The early interactions with Ulrich were electric, the two of us crossing the Atlantic to spend time together discussing how this and other chaperone systems might work. As my wife describes, we would sit in our kitchen carrying on “Gro-speak” (discussion of GroEL mechanism) until 3 AM on a nightly basis. Likewise, interactions with Paul Sigler were exhilarating – we shared a love of jazz, the Chicago Bears, the Chicago Bulls and Michael Jordan (Paul had been a faculty member at the University of Chicago before coming to Yale), and of medicine as a landscape in which biological problems present themselves. Paul, as our lab neighbour next door in the Boyer Center, taught us crystallography, step-by-step. I also spent countless wonderful hours dining, discussing, and working in lab with Helen and Kurt. Members of my group were also inspirational over these years, including, to name a few, Ming Cheng, my graduate student, a young physician who unearthed the Hsp60 mutant, Kerstin Braig who unearthed the first decently diffracting crystal of GroEL, Jonathan Weissman, who helped dissect the topology and reaction pathway , Hays Rye, who watched the components dance once they were fluorescently labeled, and Wayne Fenton, George Farr, and Krystyna Furtak, who were the bedrock senior people in my lab who carried through much of the work that underpinned our experiments.
Not least in enabling my life in science and tolerating the large time investment are my kids, Mike, who just completed an MD/PhD program at the University of Massachusetts, Worcester, studying Argonaute proteins with Phil Zamore; Annie, an artist and now a designer with Banana Republic in New York; and Dave, who is entering college this Fall. All of us share a love of tennis and have had wonderful moments together out on the courts. Mike, Dave, and I are all pretty avid about fly fishing, and probably our most memorable jaunt was to Jackson Hole to catch truly large trout (all safely returned to the Snake River). Mike and his wife Hilary have just made me a proud grandfather, and we can see a twinkle in Anabel’s eye as the next solid athlete in the family. Last but not least, my wife Martina is a paediatric cardiologist and basic scientist working on left-right handed asymmetry at Yale, who shares a love of sports, but prefers the “slippery” ones, ice skating and skiing, the latter of which all of us excel in except me – they go down double black diamond slopes while I meander down blue slopes. But we all share the same enjoyment of good food and drink at the end of a good day outside!
17 September 2012