Articles in PresS. Am J Physiol Cell Physiol (September 19, 2012). doi:10.1152/ajpcell.00299.2012
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A Tribute to L.J. Henderson, a
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remarkable physiologist, and the
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founder of the American School of
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Sociology (1878-1942)
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Gerard Karsenty M.D., Ph.D.
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Department of Genetics and Development
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Columbia University Medical Center, New York, NY
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[email protected]
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Copyright © 2012 by the American Physiological Society.
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Beware, biology is coming full circle
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“Like a machine, any organism, even the simplest, is a functional unit coherent and
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integrated.” The man who wrote this sentence is the Nobel Laureate, Jacques Monod.
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He was and remains a giant of molecular biology who devoted his entire scientific
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career to molecular bacterial genetics and therefore could hardly be viewed as a
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classical physiologist interested in vertebrate physiology. I am not even sure that the
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word physiology, let alone pathophysiology, figures once in the book from which this
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sentence is extracted (1). A book that was, at the time it was published, rather
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influential. And yet here it was, the acknowledgement that the ultimate goal of biology is
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to understand how a living organism functions as a whole, not as parts or the sum of
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parts. Modestly and lucidly the author added that, at that time (1968) we were “far to
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have, in complex organisms, elucidated the entire structure of these systems.” I do not
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believe that these sentences were written to pay lip service to human biology in order to
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attract a broader readership. Nobody really cared back then about the biology of entire
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organism. They instead reflect what a superior mind, deeply involved in cutting edge
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molecular genetics, saw as the ultimate quest of biology. At that time, 45 years ago, we
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indeed knew little of how organisms, simple or complex ones, function as a “coherent
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and integrated unit”. No one anticipated back then that we would learn so much, so fast
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and that biology would come full circle; back to where it started but now equipped with
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the tools needed to answer the issue stated clearly by Monod.
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What made this progress possible, what has allowed biology to be, at long last, in a
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position to answer questions regarding the functions of living organisms taken as a
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whole is the conjunction of two aspects of modern biology: molecular biology and
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animal genetics.
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Ever since biology became a full-fledged scientific discipline the quest to understand life
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has led to a necessary mechanistic evolution of this discipline. This required
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simplification, also called reductionism. Indeed, given the complexities of living
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organisms alluded to by J. Monod the ambition of mankind to understand how an
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organism functions as a single functional unit provoked a necessary, mandatory,
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simplification of the questions. Questions were framed not at the level of the organism
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but at the level of the organ. Subsequently, when it became possible, this simplification
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enterprise “reduced” from the organ to the cell, then from the cell to organelles, from the
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organelles to the molecules and ultimately to the genes, their functions and mode of
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action. Given the daunting complexity facing biologists, this reductionist approach was
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and, to a certain extent, remains necessary.
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Without this slow, steady, unstoppable march toward the simplest structure and the
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molecular revolution it entailed, the study of “living organisms as a functional unit
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coherent and integrated” could never have happened. This is because an unforeseen
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consequence of the intimate knowledge that molecular biology has provided about cell
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organization and function, nucleus and gene structure, cell division and mechanisms of
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homologous recombination has been to define the rules and to identify the tools
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necessary to inactivate, in any cell type, at anytime, and in many animal models, any
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gene of interest. It is this unique technological arsenal that has made it possible to study
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the interaction between organs via secreted molecules in vertebrates and invertebrates
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alike. Hence, physiology of the entire organism is in more ways than one the poster
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child of molecular genetics. It is, in a way, ironic that the most sophisticated advance of
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molecular biology, namely the ability to inactivate any gene of interest in a cell-specific
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and time-specific manner, has rejuvenated one of the most forgotten if not neglected
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disciplines of biology, whole-organism physiology.
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During the few centuries it took for biology to perform the molecular dissection of
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virtually every single piece of living organisms, the main concepts of whole-organism
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physiology were articulated. Without going back to Harvey and the realization of the
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importance of blood, one must cite the work of Claude Bernard and the notion of a
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“milieu interieur” connecting all organs (2). Half a century later Walter Cannon proposed
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the concept of homeostasis and his contemporary, L.J. Henderson, foresaw that every
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organ needed interactions with other organs in order to fulfill its functions, a concept he
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called mutual dependence.
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organism physiology (3, 4).
These concepts
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are the founding principles of whole-
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Nowadays these concepts sound pretty much like “what else is new?” but no, neither
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life nor biology started yesterday. If we place ourselves in the early 20th century when
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neuroscience was essentially an aspect of anatomy, when insulin was not even
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imagined, then we can appreciate how visionary and groundbreaking these principles
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were. Given the simplicity and yet the depth of the principles put forward by each of
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these three giants of physiology one cannot help but become curious about their lives,
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personalities and their history. I have chosen to focus on the life of Lawrence Joseph
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Henderson because he fascinates me the most, being the individual who, by far, was
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the most unusual, took the most risks, had the broader vision and the most foresight.
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Who was L.J. Henderson?
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One sees nothing remarkable when looking at a picture of L:J. Henderson (Figure 1): he
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seems to be a serious, almost too serious, upper middle class man of the early 20th
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century. And maybe he was indeed very serious, if not pompous, more than any
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academician I know or heard of but he was an intellectual maverick and a very
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courageous one. A native of the state of Massachusetts, besides a short stay in France,
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Henderson’s career took place entirely at Harvard University and its Medical School
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where, in his first life, he went to medical school, became a faculty member and rose to
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the rank of Professor of Biological Chemistry. Although L.J. Henderson was trained as
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and viewed himself as a physician and had the utmost respect for clinical medicine, he
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never practiced medicine. Instead he became a physiologist and an admirer of Claude
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Bernard’s concepts. Physiology is one of the disciplines where Henderson let his
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monomania (from 19th century psychiatry, a single pathological preoccupation in an
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otherwise sound mind) express itself. What distinguishes L.J. Henderson from his peers
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and from his time is that he did not hide it but instead used his monomania to be a
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visionary in physiology and sociology--two fields that are not often present in the same
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sentence.
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What was his single obsession? L.J. Henderson was obsessed all of his life with the
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notion of equilibrium between components of a system whether it was an organism or a
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society. Without jumping in an opportunistic manner on the current bandwagon, one can
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state that L.J. Henderson was the first scientist to propose the concept of systems
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biology although for him the “system” was the organism, not a single cell. For him no
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physiological function was achieved by a single organ, it was, instead, the end result of
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a complex network of interactions between organs what he called “mutual dependence.”
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This is what led him for instance to describe the Handerson Hasslebach equation that
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links acid base homeostasis to lung and kidney physiology. But besides this contribution
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forgotten by too many, the tragic aspect of his life as a scientist is that there was
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virtually no tool to verify this concept experimentally in the early 20th century.
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The origin of a monomania
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It is always hard to know what comes first, the chicken or the egg, and maybe it is not
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that important after all. This being said, and as mentioned above, two if not three
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pioneers of science may have helped formalize the aforementioned beliefs of L.J.
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Henderson, at least in physiology. First was Claude Bernard whose general view of
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physiology relied on the concept of milieu interieur as a relatively stable and self-
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equilibrating means to connect all organs in order to keep all physiological functions in
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check. This concept of milieu interieur allowing a proper functioning of a given organism
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(for Claude Bernard and L.J. Henderson this organism had to be a human being) was
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refined by the long-time colleague of Henderson at Harvard, W.B. Cannon who forged
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the concept of homeostasis. This concept means that all physiological functions are
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maintained in check because of the existence of concurring positive and negative
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influences on the main organ responsible for executing them.
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The other great influence on Henderson’s view of physiology, and chronologically the
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first one not exerted by a physiologist but rather by a physicist and chemist, was that of
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Josiah Willard Gibbs, whose work entitled “On the equilibrium of heterogeneous
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substances” proposed a global interpretation of physiochemical phenomena that aimed
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toward a state of equilibrium. The best way to measure the influence that Gibb’s work
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had on L.J. Henderson is to cite Henderson, “Just as Newton first conclusively showed
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that this is a world of masses, so Willard Gibbs first revealed it is a world of system” (4).
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This view of the organism as a system in equilibrium is the basis of the thinking and of
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the work of Henderson in physiology. To give full credit to L.J. Henderson one must
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emphasize that at the time, the early 20th century, endocrinology was in its infancy.
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Neither the hormones were known nor did the experimental tools exist to study their
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function even if the hormones had been identified. This is probably why recognition of
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his important work in physiology did not survive him. What really matters in Henderson’s
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double life is his thinking and the validation that sought to link two fields that he saw as
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more analogous that we usually do.
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The rebirth of a monomania
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What is truly exceptional and remarkable about L.J. Henderson is that when he was in
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his late forties and early fifties his professional life took on another dimension without
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ever abandoning or demeaning his roots and his previous identity. In the late 20’s
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Henderson was encouraged to read, in its original Italian version, Vilfredo Pareto’s
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classical work, “The Mind and Society” that had been published 10 years earlier (6).
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This was a revelation to Henderson and even more so because he saw it as an
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intellectual validation of his view of physiology. Henderson was so impressed by the
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global view of the society that Pareto proposed that he compared his work to that of
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Gibbs, which, for him, was the ultimate compliment.
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I will not discuss the work of Pareto and the notion of “residues” and “derivation” yet I
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should mention that a view of Pareto is that societies always aim at equilibrium, defined
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as “a state such that if a small modification different from that which will otherwise occur
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is impressed upon a system, a reaction will at once appear tending toward the condition
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that would have existed if the modification had not been impressed” (6). It is difficult to
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imagine a better endorsement, in another field, of the general philosophy of science
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proposed by L.J. Henderson. What Henderson saw in Pareto’s work was not only the
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notion of equilibrium but also of a reciprocal influence of groups of individuals on other
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groups. He assumed all his life that an organized society was akin to an organism and
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therefore Pareto provided him with the intellectual validation of his view of physiology--a
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view he had never been able to verify experimentally in his life as a physiologist.
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As a result of this exposure, L.J. Henderson left the field of physiology to become a
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founder of the American School of Sociology. I cannot properly evaluate his contribution
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to sociology, but it should be noted that some of his students, such as Georges Homans
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and Talcott Parsons, became leading sociologists. Based on that alone, one has to
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assume that he was rather influential and therefore expert in this nascent field. Although
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this second part of his professional life was devoted to sociology, it was used to large
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extent to prove, by analogy, that his view of mutual dependence between organs, had to
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be true since it applied in the society. Pareto was in a way a (prestigious) spokesperson
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of L.J. Henderson. What stands the test of time is this effort by Henderson to use each
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of his dual competencies to validate his beliefs and analyses in both fields. Professional
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sociologists may express reservations regarding his view of social equilibrium, likewise
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molecular biologists may, rightly so, think that even if it may be true this view of biology
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is rather superficial and ….. not molecular. Those were and remain simple but so valid
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views. But frankly, as biologists aren’t we immediately attracted by the idea that the
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society bears similarity to an entire organism? And is there any sociologist who will not
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be interested by the idea that the functioning of an organism follows many rules that
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applies to a society? Simply put, can we neglect or negate the power of the analogy
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between the organization, as a system, of a society and of an entire organism? Isn’t it
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true that our deciphering of the genome and of the functions of genes has in a great part
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validated the view of whole-organism physiology that L.J. Henderson defined
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throughout his life?
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There is more that should be said. First, at the human level. how can one not be
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impressed by the intellectual courage and honesty of this man. He certainly did not
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need to take a professional risk while at the peak of his scientific career. He could have
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remained on track and used his reading of Pareto to impress in social settings or as a
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personal source of pleasure on weekends. Instead of that, well after his 50th birthday,
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L.J. Henderson decided to begin anew, to give up a prestigious identity to build up
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another one without however, forgetting his roots as a physiologist and a physician.
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Second at the scientific level, nowadays there are only few Departments of Physiology
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in this or any country that have not added “molecular and cellular” to their name.
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Henderson tells us: “forget all that, physiology was not when it was born and will not be
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when it reaches adulthood to be “molecular and cellular” first. It was and will reborn as
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“whole-organism” physiology. This was what physiology was before the molecular era
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and Henderson who did not live through it tells us that this is what physiology will be in
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the future. Who can seriously doubt that he was, that 70 years after his death he is
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absolutely right? As a matter of fact what isn’t it Jacques Monod wrote 40 years latter?
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Functional dependence is the name of the game in physiology. Identifying, deciphering
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all these inter-organ interactions postulated by Claude Bernard and L.J. Henderson, is
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really the purpose of physiology When I first read about L.J. Henderson I thought that
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his analogy between what is an organism and what is a society was as profound as it
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was simple and deserved greater recognition, even if belatedly, if nothing else than to
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pay tribute to his intellectual courage and his foresight.
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References:
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1. Monod J. Chance and Necessity: An Essay on the Natural Philosophy of Modern
Biology. New York, Alfred A. Knopf, 1971.
2. Bernard C. An Introduction to the Study of Experimental Medicine. Macmillan &
Co., Ltd., 1927.
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3. Cannon WB. The Wisdom of the Body. W.W. Norton & Company, Inc., 1932.
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4. Russett CE. The Concept of Equilibrium in American Social Thought. Yale
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University Press, 1966.
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5. Gibbs WJ. (1876). On the Equilibrium of Heterogeneous Substances.
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Transactions of the Connecticut Academy of Arts and Sciences, 3, 108-248, 343-
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524, (1875–1878).
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6. Pareto V. The Mind and Society. Harcourt, Brace, 1935.
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L. J. HENDERSON,
HIS TRANSITION
FROM
CHEMIST TO PHYSIOLOGIST;
HIS QUALITIES
PHYSICAL
AS A MAN.
D. B. Dill
Applied
Physiology
Laboratory,
Desert
Research
Institute,
University
of Nevada
System
Boulder
City,
Nevada
89005
INTRODUCTION
L. J. Henderson (LJ) played
many parts; my account deals
chiefly with the part I knew best, that of a physiologist.
Baird
Hastings, in his biographical
memoirs of D. D. Van Slyke,
prepared
for the National
Academy
of Science in 1976,
recalled that Van Slyke had a framed picture of LJ hanging in
his office.
In Hasting’s opinion
these two good friends
“advanced physiology most” in their day.
LJ left to the history of science a superlative
legacy, his
Memories.
With the permission
of his son, Lawrence
J.
Henderson
(Larry),
I borrowed
a copy of the 265-page
Typescript from Harvard University Archives; Larry has agreed
to the selections that follow. Included are LJ’s recollections
of
events as school boy, college and medical school student,
post-doctoral
student in Europe, and as a young professor, all
as they molded his life as a physiologist
and developed his
qualities as a man. The Memories end with 1925, the year I met
him. My account of subsequent events deals chiefly with my
own observations
and what I have learned from others,
especially
from his son Larry
and his secretary,
Hilda
Richardson (now Hilda Carter Fletcher) to whom he dictated
his Memories
during three happy summers, 1937-39 at his
summer home on Lake Seymour, Morgan Center, Vermont.
MEMORIES
In LJ’s recollections
of school days one that was deeply
implanted
revolved around an algebra problem that he solved
by his own method, but his answer was rejected by the teacher
because he had not followed the rule the teacher had taught.
This aroused a strong feeling of injustice on his part, and
convinced him of the incompetence
of his teacher but he
guessed that the experience
helped develop the habit of
thinking things out for himself. His teacher of physics, Irving
Palmer, was the only one of his teachers who stood out in his
memory as not only good, but very good. Palmer, he believed,
permanently
modified his intellectual
life. Perhaps because of
Palmer’s influence he entered Harvard with a taste for natural
science and mathematics,
but with no suspicion that he had
the ability to do scientific work. He reports surprise at ending
his first year at Harvard with “fairly good grades.”
The periodic table of Mendeleev delighted
LJ. His reflections on it in his sophomore
year at Harvard gave him the
feeling there were many such undiscovered
uniformities;
such
thoughts led to his later interest in the order of nature and the
fitness of the environment
that bore fruit 20 years later.
During this year he also spent much time thinking
about
instrument
useful in
Gibbs’
Phase Rule as “a scientific
attaining a generalized description.”
While an udergraduate
he
discussed the Phase Rule with one of his teachers and came
away with the impression that he understood
it better than his
teacher did. His thinking about such matters became reveries
to which he continued
to return persistently.
He remarks on
his reveries being concerned predominantly
with external and
L. J. Henderson
taken
Business
School
in the late
in his
1930’s.
office
in Morgan
Hall
in the
Harvard
intellectual
problems, not with personal affairs and emotions.
The development
of LJ’s linguistic ability began at about
age IO when his father took him to the French colony of Saint
Pierre Miquelon.
He returned there at least three times in the
next six years, living in the home of his father’s French
business representative.
Although
there was no formal instruction in French, the several months there greatly widened his
outlook. When he was I7 he spent several weeks in a pastor’s
family near Giittingen.
Here as before he had no formal
instruction
in German and was too shy to try to speak the
language. But this shyness disappeared so that after graduation
he had no inhibitions
in his attempts to speak the languages.
Later he remarks that as soon as he could speak the most
rudimentary
French or German he talked in these languages to
himself. This practice played a role in his becoming at home
with these languages including the ability to think in them. In
the same way he frequently
found himself delivering a lecture
(without
forming
any sounds) on some topic of current
interest such as the physiological
aspects of osmotic pressure
or the equilibrium
of acids and bases in the body.
At age eighteen he had his first experience as a teacher. His
younger brother, Harry, had lost a year because of sickness; LJ
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