On the Merit of Making Comparisons

S. MARSH TENNEY

Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire

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The research I have chosen to discuss was published under the title, "Comparative quantitative morphology of the mammalian lung: diffusing area" by S. M. Tenney and J. E. Remmers, Nature 197:54, 1963. In addition to the several amusing, even bizarre, incidents that occurred in its progress, the story may be worth telling because it illustrates certain features characteristic of this class of research and of my personal incorporation of comparative physiology into a broader context of both physiology and medicine.

My early interest in physiology accompanied a strong motivation to study medicine, and in my youth, growing up in a small central Illinois town, I imagined that it was physicians who carried physiological knowledge as part of their medical wisdom. By college I had read a good deal of physiological literature and was deeply influenced by the works of Jaques Loeb, by D'Arcy Wentworth Thompson's classic, On Growth and Form and by J. B. S. Haldane's, On Being the Right Size. Although my naiveté about a necessary relation of physiology to medicine had vanished, I clung to the idea that a medical education would provide a breadth of knowledge that I sought, and that physiology and clinical research had much in common. It was my special conviction that comparative physiology offered a unique avenue for expanding the concept of interrelatedness even further. Quirks of evolution introduce features that invite comparison with other species and even with dislocations and perturbations in the human condition. The game of searching for differences in similarities and similarities in differences is an intellectually satisfying one that can lead to a deeper understanding of the evolution of a physiological process.

My plan to become a fully trained physician first was nearly derailed by my enthusiasm for physiology and led to misunderstanding by the dean of medical students at Cornell. When approached by William S. McCann, chairman of the department of medicine at the University of Rochester's Strong Memorial Hospital regarding my qualifications for an internship, he volunteered: "You don't want him. He wants to be a physiologist." To this Dr. McCann fortunately responded: "Good. I'll take him." (This interchange was told me several years later by Dr. McCann.)

Consequently, I became immersed in residency training at the University of Rochester, interrupted by two years' service in the navy and, after nearly five years of clinical work, I was anxious to try my wings as a physiologist. In 1950 I relocated to Dartmouth, where I completed an electrophysiological study of the moth heart with emphasis on its periodic reversal of beat, a uniquely Lepidopteran phenomenon. The work was subsequently publishedmy first. The study was also a prototype of my mingling of comparative physiology with general physiology and clinical phenomena. In brief, conduction in the moth heart bore a close resemblance to that in the mammalian atrioventricular node, and its normal rhythm was similar to the clinical arrhythmia, reciprocal rhythm. Was it, therefore, a model?

Invitation from Dr. McCann in 1951 to return to Rochester to join his department was promptly accepted, and once there I was given a laboratory of the department of medicine but physically located in the department of physiology. Soon thereafter I was given a joint appointment in physiology and experienced the profound benefits of contact with two extraordinary men, Wallace Fenn and Hermann Rahn, whose counsel, advice, and wisdom were a constant inspiration. By good fortune I had obtained an NIH grant with such an all-encompassing title that I could roam widely in the cardiorespiratory field. This was an enlightened era when NIH policy was permissive and investigators could follow their own leads. What counted was the progress report. In addition to joint projects with fellows in the laboratory, I had numerous collaborations with others in the department of physiology, and published on topics including clinical arrhythmias in man backed by a study of experimental arrhythmias in the turtle heart; low ventilatory responsiveness in respiratory failure alongside high responsiveness in ventilator-induced hypocapnia and hypocapnia at high altitude (I accompanied Hermann Rahn on his Mt. Evans expedition); the origin of ballistocardiograph waves in health and disease that included both a study of subjects with congenital ectromelia who were recruited from the freak shows of carnival and circuses to determine the role of reflected waves from the extremities; and a study of large tortoises in comparison with dogs of equal weight to distinguish the relative contribution of stroke volume from ejection velocity.

By 1956 the pace of the preceding five years forced a reassessment, because the responsibilities of serving as an assistant attending physician on the wards, as a codirector of the heart station, and as a teacher of classes in medicine for third and fourth year students were straining my limits. Something had to give. Since I liked everything I was doing there was no easy choice, but the pull of physiology dominated, in part because I had stored a growing number of research questions, almost all of which were in the realm of physiology. The situation was made easier when the provost at Dartmouth came to Rochester and invited me to be chairman of the department of physiology in their medical school and to take the lead role in developing, not only that department, but all the other basic medical sciences as well, creating what would amount to an entirely revitalized institution. Of course, it turned out that I was busier than ever, but there was a dramatic change in my responsibilities which had an energizing effect. One of the educational innovations we introduced was a year out program for medical students, the time to be spent in research with a faculty member. In 1960 John Remmers elected that option, and together we set about selecting an appropriate project.

The idea of an animal matching its pulmonary diffusing capacity for oxygen to its metabolic oxygen uptake rate seemed a reasonable hypothesis for optimal design of the lung. We decided to explore the hypothesis by making a comparative study, selecting mammals across the full range of body size shrew to whalestudying the lungs morphometrically, and analyzing the results using the method of allometry (the biology of scaling). The assumption was that pulmonary diffusing capacity would be proportional to the internal surface area of the lung (total alveolar surface area). Relevant variables would also include lung volume, alveolar size, and alveolar number. The relationships with body size and also with metabolic rate would be established, a function well known not to be proportional to body size (mass) but to its 3/4 power. The crucial tactic in our comparative approach would be to include those few animals whose metabolic rate was below the standard predicted from body size, because, if our hypothesis had merit, these unique animals should fit into the general pattern relating pulmonary surface area to metabolic rate, but not be proportional to body size. The problem would be to acquire lungs from these few exotica and from their appropriate controls.

It was at that stage that the adventure that characterizes all research took on its more literal meaning. For example, trapping local species of bats and shrews was complicated by the special problem of overnight starvation in the field traps; and obtaining a local black bear required the help of a bounty hunter who introduced us to his arcane occupation and its ancillary rewards (selling carcasses he had stored in his deep freeze to frustrated hunters who carried them home in triumphant display as evidence of their hunting prowess). The aquatic species posed more difficult problems. We wanted a whale for the largest body mass, and for the low metabolic rate mammals we had a sloth to compare with a raccoon for matched body size, but we also needed the sluggish manatee and dugong for comparison with the very active porpoise.

Friends and good luck came to the rescue. Hermann Rahn, who was on an expedition in the Indian Ocean, sent a fixed dugong lung and John Lilly helped us locate a porpoise. A late night news report mentioned a beached whale at Newport and before dawn John and I were on the road laden with saws, grappling hooks, rope and an axe. It didn't take long to locate the whale, but our hearts sank when we saw that the carcass had been opened. Fortunately, only the heart had been removed and the lungs appeared to be undamaged. Sometime along the course of our work I put a ladder up the side of the beast. Being unaware that anyone was on the other side I was startled at the top to come face to face with Dick Backus from Woods Hole, a friend I had not seen in over twenty years. We chuckled over the legendary meeting of Stanley and Livingstone. The fact that the lungs could not be wholly contained in our tubs led to domestic unhappiness. Back in Hanover everything was unloaded, the lungs were suspended from a high ceiling and kept inflated with compressed air, and the back of the station wagon was cleaned. We overlooked the fact that a considerable amount of blood on the journey from Newport had splashed onto the floor and drained into the underlying well that held the spare tire. A few weeks later as the putrefaction process was well underway there was no doubt that something was amiss. In spite of all efforts to clean up and de-odorize the stench remained, and we were never again able to drive that car with the windows closed.

The search for manatee lungs began with a plan to study a live manatee that was a prize exhibit in a small private enterprise in southern Florida. All went well, and the work was completed without incident. (Actually, the primary interest of that study was electrocardiography, because the manatee, like all Sirenidae, is unique in having a bifid ventricle, and that odd feature raises some questions about the morphogenesis of the QRS complex.) More good luck came with a phone call from the Florida Wildlife Service (with whom I had kept in constant contact) telling me that they had a dead manatee and that I could have it for dissection. I returned to the laboratory feeling triumphant, and John and I were now confident that we would obtain representatives of all the species that we required. Joy turned first to sadness and then anxiety as communications from the owner of the live manatee that I had studied had died three days later, and the working hypothesis was that something I had done had killed the creature. Many stressful days later it was proven that a commercial zoo competitor had poisoned the animal, cleverly timing his mischief to set me up as the malefactor.

After all the data had been gathered and analyzed it appeared that only lung volume was proportional to body mass, making it the only pulmonary measurement consistent with the theory of similitude (comparative physiology's borrowing of Newton's law of similarity which states that models must be functionally and dimensionally similar to the structures they represent). Alveolar size and diffusing surface area certainly did not comply, but it was satisfying to find that surface area was proportional to metabolic rate, our basic hypothesis.

Shortly thereafter Ewald Weibel and colleagues repeated our study with measured results essentially the same as ours, but their regression analysis led to a proportionality of pulmonary surface area to body mass. This was a rattling conclusion for us until it became clear that Ewald had included none of our uniquely low metabolic rate animals in his series. We felt that these particular animals were the lynchpin of our comparative strategy, but Ewald felt that including aquatic mammals was inappropriate. In fact, omitting all aquatic mammals and the sloth from our series led to a regression slope that was the same as Ewald had found in his data. Thus, neither differences in measured values or mathematical analysis was the root of the problem. It was simply a difference of opinion regarding selection, or exclusion, of particular species. Without discussing some of the mathematical incoherencies of related variables if pulmonary surface area is proportional to body mass, the issue has been labeled the "allometric paradox," and its resolution is not clear. However, there has been a good deal of imaginative speculation, all of which bodes well for further research. "Truth is more likely to come out of error, if this is clear and definite, than out of confusion" (Francis Bacon).

	Footnotes

Correspondence and requests for reprints should be addressed to Martin Tobin, M.D., Division of Pulmonary and Critical Care Medicine, Edward Hines Jr. Veterans Affairs Hospital, Route 111N, Hines, IL 60141.