Robert Kellogg Crane: A scientist remembers

Authors


I was born on December 20, 1919 at 700 Highland Avenue, Palmyra, New Jersey. My father was Wilbur Fiske Crane, Jr. a highly regarded farm building architect and engineer among whose prominent clients were Nicholas Roosevelt near Monck's Corner, South Carolina, Joseph Pew near Philadelphia, Lammot Dupont Copeland near Betterton on Maryland's Eastern Shore and the Haxton Canning Company of Oakfield, New York. Then came World War II and my father's very successful business was brought to an abrupt halt when President Roosevelt, to focus effort more directly on the war, signed an order limiting farm building construction or repair to no more than $5000. My mother was Mary Elizabeth McHale Crane.

Illustration 1.

I started kindergarten nearer six than five because of my late December birth date. I continued in the Palmyra public schools, skipping the second grade, through the second year of high school when I was given the opportunity to apply, by examination, for entry and a scholarship to St. Andrew's School in Middletown, Delaware. I was accepted though I was put back a full year based upon the actual knowledge I had acquired in Palmyra where I was on the honor roll. I spent three years at St. Andrew's. I received superb schooling especially in English as taught by William Cameron. I graduated in 1938.

In the fall, I enrolled in Washington College, Chestertown, MD. I have already written the history of my college years and the following years up to 1962 in (1). Here, I will mention only a few highlights.

To satisfy a curricular requirement, I enrolled in Chemistry for my freshman year. Up until then I had developed little interest in science but I found the lectures by Kenneth Buxton compelling and complete, no book was actually needed. One thing led to another and I ended up taking all the chemistry courses and branched out to do nearly the same with biology under Julian Corrington and physics under Jesse Coop. It should also be noted that the German I acquired from Arthur Davis let me pass the examination required at that time for graduate students in science at Harvard with barely a month's review. I graduated in 1942 with a B.S. in chemistry and minors in both biology and physics.

Kenneth Buxton steered me toward a job with the Reynolds Experimental Laboratory of the Atlas Powder Company in Tamaqua, PA, where the training program was designed to provide supervisors for the TNT plants at Paducah, KY and Weldon Springs, MO. The intensive course turned me into a competent analytical chemist. I was kept on at Tamaqua after the training course was over. For the next few months I spent my time analyzing ethylene glycol dinitrate fumes in one of the dynamite mixing houses. I did no research.

Toward the end of my first year, I was offered a chance to teach chemistry at the Northeast Missouri State Teachers College in Kirksville, the permanent staff having all gone off to the war. I accepted and spent the next year teaching every course in chemistry by myself, but probably not too well. We used books and on occasion I was only a few pages ahead of the students. Along the way, however, I decided I should get directly into the war effort.

I applied for a commission in the U.S. Navy and then volunteered for the draft. With the help of some broad hints from the non-commissioned officer in charge, I was able to pass the Eddy Test designed to assess knowledge and aptitude for electronics and was sent off to Great Lakes Naval Training Station as a seaman 1st class. Toward the end of the ninety days training, my commission came through and I was sent to the Officers Training School at Plattsburg, NY for another ninety days. I was in much better physical condition than most of the other officers who had come directly from civilian life. I was appointed battalion adjutant probably because of a military bearing acquired at Great Lakes.

After graduation, I was sent to Norfolk, VA and then to Hollywood Beach, FL for training as a Combat Information Center Officer. A week or two later, I became very sick with joint pains and severe night sweats. Unable to diagnose me, the medical staff labeled me as malingering. With the help of tablets containing aspirin, phenacetine, and caffeine, I was able to keep going on my own until I completed the course and returned to Norfolk, where I was immediately placed in sick bay and then transferred to the Portsmouth Naval Hospital. There it was determined that I had meningococcemia and was placed on a regimen of penicillin which was quickly effective.

I spent several months in recuperation and was then sent to Hunters Point near San Francisco to become a deck officer on the USS Killen, DD593 (a subject in Wikipedia). Killen had two years of active service. The first year ended with her taking a bomb at Surigao, during the battle of Leyte Gulf. The second year began after repairs at Hunters Point, and I was with her until she was docked at San Diego for decommissioning. While I was aboard, Killen went off to the Philippines where she was part of the anti-submarine screen for the cruiser carrying Douglas MacArthur to nearly every island in the chain to give his “I have returned” speech. Later, Killen provided fire support to the Australians fighting the Japanese in Borneo. The war ended and after supporting the occupation forces in Japan for a time, she was sent back to the United States.

After being released to inactive duty, I want off to graduate school at Harvard in the medical science program at the medical school in Boston, there being no biochemistry in the main campus in Cambridge at that time. There were few to choose from as preceptor for a thesis; Ralph McKee had just left, Chris Anfinsen was in process of leaving, Claude Villee was heavily occupied with his excellent book, and Baird Hastings was taking no graduate students. That left Eric Ball who offered to take me on provided I would study C14 incorporation into retinal tissue. I accepted and spent a little over two years on the project until I was allowed to accept an offer from Fritz Lipmann to be the Assistant Biochemist at the Massachusetts General Hospital.

I spent a year with Lipmann and got very little done experimentally but got great exercise for my brain and my imagination. When he was home, Lipmann formed the habit of coming into my cubby hole laboratory next to his office every afternoon about 4 o'clock and starting a conversation on one or another scientific subject. Through the good offices of Maurice Krahl, Carl Cori showed up about mid-year, looked at me, nodded his head and shortly after I received an invitation to join his department in the medical school of Washington University in St. Louis.

I was appointed an instructor in Cori's department and set to work on a variety of projects with a number of colleagues. Approximately, the first two and one-half years were spent with Alberto Sols on hexokinase. I was raised to Assistant Professor. Then Alberto went home to Spain and Richard Field showed up from Boston. We worked on transport in Ehrlich Ascites Tumor Cells until Richard left and then Cori, and I joined efforts to produce what some (e.g., Erich Heinz of Frankfort) felt was the definitive study at the time (2).

Shortly after, I broke with Cori and set off to study the active transport of sugars by the intestine. First with Stephen Krane and then with Ivan Bihler, we were able to demonstrate that covalent bond formation was not a part of the mechanism. With David Miller, we identified and isolated brush borders. I became an Associate Professor.

I have described our early efforts in my article in Psychological Reviews (3). Finding that sodium ion was essential for sugar active transport and knowing that animal cells continuously pumped sodium ions out. I was convinced that this was the needed energy source and wrote in that article (p. 817) “coupling of sugar absorption with Na+ transport has seemed to hold attractive possibilities as a mechanism” but how was this coupling accomplished? I spent over a year considering various possibilities but arrived at the solution while attending a symposium on membrane transport and metabolism in Prague only hours before it was my turn to lecture the assemblage. I proposed a coupling between the fluxes of Na+ and glucose made possible by their attachment to the same, reversible transporter as shown in Fig. 1. I displayed Fig. 1 to the assemblage. Peter Mitchell reacted with the outburst, “you've got it” as I have described in The Road to Ion-coupled Membrane Processes. In the Living History Project of the American Physiological Society (on the web, see the-aps.org/living history/crane), I have also described the largely successful efforts of some, particularly Mitchell, himself, Bruce Weber and John Prebble, to give credit to Mitchell for the concept of flux coupling as in Fig. 1.

Figure 1.

Copy of R. K. Crane's notes drafted on August 24, 1960. Later drawn more formally and added as an addendum to reference (4).

Having no antecedent, it took some years for the concept that I have called “cotransport” to be generally accepted although Peter Mitchell understood it immediately, as I have described. From that time on, I did little else experimentally but to try to prove or disprove my proposal. Two years later, I accepted the Chairmanship of Biochemistry at the Chicago Medical School. John Scheinin, the president of the school, was somewhat persuasive but what really caught my interest was Philip Shubik and the handsome new research building constructed by the National Cancer Institute. I thought there was great potential.

Arne Dahlqvist arrived as a post-doctorate fellow and, together with colleagues from other local institutions, we accomplished some interesting work on lactose malabsorption (5,6).

However, only 4 years after my arrival, I decided that the potential was not going to be realized and I left to accept the Chairmanship of Physiology in the brand new Rutgers Medical School.

During the twenty years I spent at Rutgers, my colleagues and I pursued an absolute proof of cotransport without being able to achieve it. I spent a lot of time dealing with the problems of developing a medical school from scratch. I fought to establish the departmental chairmen as a meaningful force and won. I was asked to lead an effort to keep the medical school within Rutgers; we lost. Next, I was asked to lead the faculty into a union, and I did. Then, I was asked to help with the preparation of by-laws for the College of Medicine and Dentistry of New Jersey to which we now belonged and I did. I retired in 1986 and turned my attention and labors for the next ten years to develop a horse farm devoted to my wife's interest in dressage.

Absolute proof of my proposal of cotransport has finally been achieved. By means that, having been out of science for more than 20 years, I am actually not qualified to judge, the peer reviewers have made their judgments, I can only applaud. There is Ernest Wright's group's crystallization of a cotransporter and demonstration that it acted in the predicted fashion (7) (see also The Wright Lab on the Internet). Then there was Forrest and Rudnick's crystallization of a bacterial amino acid transporter (LeuT), a determination of its amino acid structure, and a demonstration that transport could be achieved by a process of folding (8). Now we have the crystallization of both the outward and inward facing species of another cotransporter by Shimamura et al. (9) with the demonstration that folding of a kind similar to that suggested by Rudnick will provide for transport.

How was I able to get to the concept of Cotransport which at the time was completely new, never proposed before? I have done a lot of thinking and talking to my wife of forty years, Laura J. Crane, Ph.D., who was also a biochemist, about this question. The answer seems to lie in the fact that, aside from being a biochemist or physiologist, I am a problem solver. It does not matter in which genre of inquiry I am involved, my approach is always the same, step by step until the end is achieved, and has been for a long time. My teacher in the 7th grade of elementary school, Miss. Ida Bonsal, tried to teach us how to solve problems and, with me at least, she succeeded so well that when I was in high school at St. Andrew's I sent her a “thank you” letter.

Peter Mitchell, on the other hand, is described quite differently in the many articles that have been written about him. I will discuss just one to be found on the web at http://www.life.illinois.edu/crofts/bioph354/mitchell.html entitled Peter Mitchell (1920-1992). But first let me go back to 1964 when I visited Mitchell in Bodmin and signed my name on the first line of his, as yet pristine, record of visitors. We discussed nothing during the evening but the next morning he showed me copies of pages 158 and 159 from his article in ref. 9. He claimed on the first page that I had only hinted at the coupling between the fluxes of Na+ and glucose and, on the second, he showed flux coupling exactly as I had formulated it although it looks slightly different because the figure was drawn by a different draftsman and, most importantly, he changed the name to Symport. I protested that I had not just hinted at flux coupling but had stated it precisely. Mitchell shrugged.

There was nothing I could do about it, not in those years before personal computers, the internet, and the world wide web. Journals, then as now, did not provide a means of seeking relief from the not entirely true to the most egregious of falsehoods which they may have printed and made a part of the public record. This gave Mitchell an advantage. He also had another advantage. At St. Andrew's, Mr. Cameron required us to write, twice each week, a three hundred word essay. I always finished what I wanted to say in about half that much or less and then had to go back and pad my composition to meet the requirement of length. Still today, it is the way I write. Mitchell, on the other hand, had a great ability with words and phrases and was able to link his thoughts about bioenergetics to his philosophy (10). I had no philosophy.

In the Crofts article referred to above, it is stated that Mitchell had an “unfailing habit of giving credit where credit was due.” This is certainly not true in my case and Bruce Weber reports (personal communication, email of 3 17, 2009) on criticizing Mitchell “for not citing work that had influenced him as he should have done out of professional courtesy at a minimum.”

In constructing his second version of his chemiosmotic hypothesis (11), Mitchell was able to draw upon my proposal of cotransport and the theory of oxidative phosphorylation proposed by Davies and Krebs nine years earlier which Mitchell did not change very much while adopting it (12). I think it must be clear by now that if you have not read the original literature you cannot know what transpired in the years from 1957 to 1963; too much has been written since without reference to the original articles. In particular, is this true of the proceedings of the Prague symposium which is a book not readily available even in substantial libraries? If you choose to search out the originals help is available. You can apply to my grandson, Armando Navarro at MailNavarro-1@ Yahoo.fr or directly to me at rcrane5800@aol.com for copies of, for example, the articles by Mitchell and by me printed in ref. 14.

Ancillary