弗朗兹— 乌尔里奇• 哈特尔教授自传 (只提供英文版)
I was born on March 10th, 1957 in Essen, Germany. My father was an electrical engineer and my mother was trained as a domestic science teacher. When I was four years old, the family moved to the northern part of the Black Forest where I grew up in a small village. I had a wonderful childhood, roaming the fields and woods with the neighbours’ children, collecting frogs and salamanders and building dams in the little brook near our house. When I was five, I learned to read musical notes and to play the recorder, later the flute and piano. After attending the small village school, I went to gymnasium (high school) in the district town of Pforzheim, where I developed two major interests, music and biology. The latter was spawned by my grandfather, a competent hobby microscopist, and by a family friend who was a biology teacher. He took me on field trips and taught me how to identify and collect insects. I was fascinated by the variety and beauty of butterflies and moths, and accumulated a substantial collection which I still keep in my office today. During the final years at high school I became very excited about biochemistry, the field that would become my vocation.
I joined Medical School at Heidelberg University at the age of 19. While attending mandatory classes in my ‘spare time’, I worked on my doctoral thesis in the Biochemistry Department. I discovered that a class of liver cell organelles, the peroxisomes, could be metabolically activated and induced to proliferate by thyroid hormone. My thesis was sent to the renowned biochemist Walter Neupert at Munich University for grading, who then invited me to join his laboratory as a postdoc – an amazing opportunity that I did not let pass. Although I completed my MD degree, I never practiced medicine but instead devoted myself to research.
The move to Munich turned out to be crucial, both for my professional and personal future – the latter because in 1986 Walter Neupert allowed me to attend a molecular biology summer school on a Greek island where I met my future wife Manajit. Walter’s group studied the process by which mitochondria, another class of cell organelles, import newly-synthesized proteins. Evidence was mounting that so-called heat-shock proteins, such as Hsp70, had to stabilize these proteins in an unfolded state for translocation across the mitochondrial membranes. But how did the proteins fold into their functionally active forms once inside the organelle? Clearly, this was a fundamental question in biology and the mitochondrial system provided the opportunity to study it. In pursuing this problem I was fortunate that Walter introduced me to Art Horwich, a young geneticist from Yale. Using a combination of genetics and biochemistry, we discovered that the mitochondrial protein Hsp60, a molecular chaperone, mediated protein folding in an energy-dependent process. This discovery, published in two collaborative Nature papers in 1989, marked the radical deviation from the then prevailing view that proteins folded spontaneously, without any help by cellular machinery or an energy source.
To gain experience abroad, I interrupted my time at Munich University and spent almost a year with Bill Wickner in Los Angeles to work on bacterial protein export. While in Bill’s lab I had the opportunity to explore various professional opportunities and eventually I accepted an offer from Memorial Sloan-Kettering Cancer Center to join the newly-founded Department of James Rothman as an Associate Professor. In 1991 my wife and I moved to New York, and this marked the beginning of our long-term collaboration. The following years were intense and full of exciting discoveries. My colleagues and I dissected and reconstituted the evolutionary conserved pathway of protein folding in which the Hsp70 and Hsp60 chaperone systems cooperate sequentially. We discovered that Hsp60, exemplified by bacterial GroEL, functions as a cage for single protein molecules to fold unimpaired by aggregation, and we demonstrated the significance of co-translational folding for the biogenesis of large multi-domain proteins. In 1993 I was tenured and promoted to Full Professor and in 1994 became an investigator of the Howard Hughes Medical Institute.
In 1997, I accepted the offer to become one of the Directors at the Max Planck Institute of Biochemistry in Martinsried near Munich. Over the past 15 years we have investigated the Hsp70 and GroEL mechanisms in more depth using structural and other biophysical approaches. We have conducted a systematic analysis, by quantitative proteomics, to understand how the cellular proteome utilizes the chaperone network for folding and conformational maintenance. We have also discovered that activating the chaperone system can prevent the formation of protein aggregates that cause neurodegenerative diseases, such as Huntington’s or Parkinson’s disease, and have provided evidence that such activation can be achieved with an experimental small molecule drug. In current research we wish to understand why cellular chaperone capacity declines during aging and how the system can be re-set to a more youthful state. Much work still lies ahead!
For many years I have had the privilege of collaborating closely with my wife Manajit, a first-class biochemist who has contributed to many aspects of our research. I have worked with a long list of highly gifted students and postdocs. They deserve most of the credit for the achievements of my laboratory and it gives me great joy to observe that many of them have advanced to successful independent careers in science.
17 September 2012