San Diego State University

Chemistry and Biochemistry

My Mentors

I've been extremely lucky in having the opportunities to work with brilliant people who have shaped an entire research field. Here are my personal remembrances and tributes to my mentors.

My thesis advisor is Professor Anthony Norman of the University of California at Riverside. Tony was fresh out of the University of Wisconsin when he came to UCR and was interested in the mechanism of action of vitamin D. Tony just succeeded in the synthesis of radioactive vitamin D, which meant that the path of vitamin D could be followed in an animal receiving physiological, rather than pharmacological, doses of the vitamin. Tony suggested that I determine the target tissue of tritiated vitamin D in ricketic chickens. I was foolish enough to think of the project as being too physiological, and went off to a project totally unrelated to vitamin D! My thesis research, which was concerned with deoxyribonucleotide synthesis, still involved scraping yards of chicken guts-the source of fast growing mucosa cells, and earned me a membership in the prestigious "One-Mile Club" (there is also a "Five-Mile Club"). Tony's research is responsible for defining the role of vitamin D-derived 1,25-dihydroxycholecalciferol as a hormone and is the founder of the field. He is still busy with research, organizing meetings, and publishing books.

In his first year as a faculty at UCR, Tony taught a graduate course on oxidative phosphorylation while commuting between UCR and UCLA discovering phosphohistidine with Paul Boyer. One of the readings he assigned for the course was "Mechansims in Bioenergetics" by Efraim Racker. Ef's enthusiasm for bioenegetics was so palpable and infectious that I decided to write to him, among others, for a post-doctoral position. Maybe the fact that Tony had worked with Boyer had something to do with Ef's decision to accept me into his lab. When I showed some hesitation about leaving California and told Tony that I was waiting to hear from other labs on the West coast, Tony told me that I should jump at the opportunity because Ef was a "big fish." So off I went to the East coast, a decision that set the course of my scientific career.

I worked with Ef for seven years at Cornell, from 1968-1970 and 1972-1977. This was considered too long for a post-doc by the standard of by-gone days, but I would not have traded the experiences for anything else. Ef was the most brilliant man that I've ever met and I felt privileged to be part of his group at the peak of his career. Ef's life was recounted in an article by Jeff Schatz: "Efraim Racker: 28 June 1913 to 9 September 1991" (Comprehensive Biochemistry, 40, 253-276). Ef had about 20 post-doc fellows from different parts of the world at any one time, and I'm sure each of us remembers him in a different way. In retrospect, it was amazing that there was little disharmony in his very large group partly because each of us had our own projects. Ef was demanding of us, but no more than of himself. His office door was always open and he had his own bench area in the lab, which was next to mine from 1972-1977. I witnessed the famous experiment (Racker and Stoeckenius, JBC, 249, 662-663 (1974)) that demonstrated ATP synthesis driven by proton gradient, using vesicles reconstituted of bacteriorhodopsin and mitochondrial FoF1, thus resolving a long-standing controversy. The experiment was performed by Ef himself using an ordinary pH meter in a single afternoon, while Dr. Stoeckenius looked on. The simple beauty of the experiment has never ceased to awe me.

My first project at Cornell was the resolution of a coupling factor of beef heart mitochondria. This was shortly after OSCP (oligomycin sensitivity conferring protein) was isolated. My first year ended in total failure, however, I did manage to tear F6 away from F1 in the 2nd year. I'm quite proud of the fact that while several other coupling factors have fallen by the wayside, F6 has been proven to be an integral part of FoF1. It was a great pleasure for me to see that the three-dimensional structures of both OSCP and F6 were resolved recently.

My project during my second stay in Ef's lab was reconstitution of the Ca pump of sarcoplasmic reticulum. Yasuo Kagawa had developed the technique of proteoliposome reconstitution and it was being applied to the reconstitution of oxidative phosphorylation with isolated mitochondrial components. Ef then expanded this research to the different ATP-driven membrane transporters. Ef's fame spread far and wide, and many scientific luminaries visited his lab in spite of the fact that Ithaca was an out of the way small town in upstate New York. I remember Peter Mitchell sitting in on our lab meeting, and working with Gobind Khorana on an idea of his, which resulted in a JBC paper. In addition to these dignitaries, my lab life was enlivened by the many talented and colorful fellow post-docs who went on to have their own illustrious careers: Don Schneider, Carol Cunningham, Maurice Montal, Bernie Trumpower, Charlie Yocum, Dennis Lang, Chris Miller, Gera Eytan, Nathan Nelson, Baruch Kanner, Ramon Serrano, Bill Dubinsky, Ed LaBelle, Piotr Zimniak, Judy Belt, and Marcelo and Ramona Alfonso. We were all, at one time or another, taken under the wings of Anne (Kandrach) Ghiorse, Ef's right-hand woman. Sadly, Anne passed away a few years ago.

It was also at Cornell that I met Leon Heppel (see a "Reflections" article in JBC about Leon by Maxine Singer, JBC 278, 47351-47356 (2003)). I remember him coming back from his sabbatical in London being very excited about his finding that extracellular ATP caused permeability change in transformed cells. I could not have predicted that, years later, I would be devoting considerable efforts on the enzymes that are involved in terminating purinergic signaling, the ecto-ATPases.

My other mentor is Harvey Penefsky. Harvey and Maynard Pullman isolated the mitochondrial ATPase, F1, while working with Ef. Unraveling the mystery of F1 became Harvey's lifetime work. It was in his lab at the New York Public Health Research Institute (1970-1972) that I resolved the 5 subunits of beef heart F1. It was another piece of research that brought great satisfaction. I have sometimes wondered how my career would have turned out if I had not left the field of F1.

In spite of his influence and respect accorded him by other F1 researchers, Harvey has always been a modest man. One could not have asked for a better boss, who was understanding and patient. I never felt pressured in getting my work done even though Senior and Brooks were going after the same prize, which I didn't find out until later. Harvey is a hands-on person and is a genius in devising and constructing analytical apparatuses, which allowed him to address mechanistic questions that would not have been possible otherwise. From Harvey, I learned that it is possible to do great science without a large group. But of course, one would need to have Harvey's intellect to pull it off. In 1994, I enjoyed Harvey and Zia's hospitality again in his lab at the SUNY Health Science Center in Syracuse. I had the opportunity to learn of all the progress and controversies in F1 research and I was extremely pleased that I was able to write another Knowles and Penefsky paper.

After Cornell in 1977, I spent several years working at UCSD as an independent research scientist in the lab of another great biochemist, Nathan Kaplan. In spite of his manners of absent-mindedness, Nate was a major moving force behind many great endeavors in biochemistry. Besides his work on pyridine nucleotide-linked enzymes, Nate was best known for launching "Methods in Enzymology" with Colowick. Nate's influence and extensive network in the scientific community was obvious in a memorable symposium that he organized to pay tribute to Martin Kamen. I had never seen so many Nobel Prize laureates and famous scientists at one gathering than on that occasion.

When I arrived at UCSD, Nate and Gordon Sato just received an NIH grant to establish a nude mouse colony for cancer research. I was again thrust into a large and bustling group of colorful and fun-loving people who were also doing first-rate research. In the early 1980's, Nate was enthusiastically talking about the first biotech company in San Diego, Hybritech. But even Nate could not have foreseen the astounding growth of the biotech industry in San Diego in the ensuing two decades. He would have been proud of the fact that several of his students have since founded their own successful companies.

The culture of academic life has changed considerably since my days of apprenticeship. I feel nostalgia for those days for many reasons and I treasure the friendship and camaraderie of my colleagues. Most of all, I'm grateful to all my mentors for showing me the enjoyment of doing science.

-- Aileen F. Knowles

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