KEITH Miller represents a most uncommon species, the result of the proverbial “three body collision” of the right attributes that yield a rara avis: innate curiosity, a prepared mind, and chance, when alloyed in a single individual in the right environment, moves an entire field through seminal discoveries. Keith Miller was born in the United Kingdom in 1941. He overcame an initial interest in history and, at age 16, as required in the United Kingdom system for advanced education, selected science over art and planned a career in science education. He passed the qualifying examinations for Oxford and, in 1960, was admitted to St. Catherine's College. In the Oxford system, tutors are assigned by college and, as chance would have it, E. B. Smith, Lecturer in Physical Chemistry, became Miller's tutor. Keith Miller became a “favorite son” of Dr. Smith, as they shared a common avocation in hiking and rock climbing, and were both active in Oxford's Mountaineering Club. After the general 3-yr chemistry course, the fourth year at Oxford is committed to research. His Bachelors Degree thesis was titled, “Properties of Gases in Solution,” a topic suggested by his tutor based on conversations with Professor Joel Hildebrand, of the University of California, Berkeley, at that time the world's greatest solution chemist. Smith had just spent a summer in the laboratory of Hildebrand, who long before had suggested to the U. S. Navy the use of helium for deep diving because of its low solubility in water. Because carbon tetrafluoride is even less soluble in water than helium, Hildebrand suggested that, theoretically, it should attenuate the problem of “bends.” On his return to Oxford, Smith assigned the topic of studying the solubility of fluorocarbons in water to Keith Miller, and so began a career of science relative to our specialty. (Figure 1).
Stimulated by this research, Miller accepted Dr. Smith's invitation to pursue a D.Phil. degree by joining the newly formed Interdisciplinary Group on “High Pressure Biology” with Professor Sir William Paton, Chairman of the University Department of Pharmacology. In the early 1960s, Linus Pauling and Stanley Miller independently described a clathrate theory of anesthesia. Keith Miller's D.Phil. thesis, titled “Molecular Interactions,” demonstrated that CF and SF fit the lipid theory better than the Pauling/Miller hypothesis did, and his related paper, entitled “The Site of General Anesthetics,” was published in Nature in 1965. .
He followed his time at Oxford with 2 yr as a National Science Foundation Fellow in Hildebrand's laboratory in Berkeley, studying the diffusion and solution properties of inert gases. By 1969, when he returned to Oxford, Miller had already published ten papers, nearly half of which appeared in the journals Nature and Science, and all concerned various aspects of the physical chemistry of gases and anesthetics.
That summer, he attended a diving physiology conference in Philadelphia. In 1964, Miller had met the anesthesiologist Dr. Robert Epstein at Oxford, who was then on sabbatical leave from Columbia University. He now accepted Epstein's invitation to give a research seminar at Columbia before flying to Bolivia to scale 20,000-foot Huagna Potosi in the Andes. At a house party on the evening before his departure for South America, I had a chance meeting with Keith Miller on a back porch, where we both attempted to escape the din and smoke. I reported a recent decision to assume the Chair of Anaesthesia at the Massachusetts General Hospital and described plans to commit a significant research effort in the Anaesthesia Department to the elucidation of the fundamental mechanisms of general anesthesia. I asked whether his 2 yr in the United States were satisfying enough that he might consider becoming a major component of the effort in Boston, and he agreed to consider the opportunity.
Later that summer, he joined me in Boston, inspected the resources I was planning to commit to this venture, and interviewed with members of Harvard's Pharmacology and Anaesthesia Departments. In the late fall of 1969, we consummated the arrangements in Heathrow Airport while I was changing planes on a return flight from Stockholm to Boston. To us, this represented a mutual and unusual “act of faith,” without protracted and written negotiations and sealed with a handshake. During the course of his many climbing expeditions with the Oxford University Mountaineering Club, he met Janet, then a D.Phil. candidate in Biochemistry at Oxford. They were married in 1970 and have two children, Neil and Nicholas, now aged 18 and 20.
Miller's research plans were folded into the competing renewal application of the Harvard Anaesthesia Center for Research and Training, a large, National Institute of General Medical Sciences-funded Center grant. His projects have been funded continually by the Center ever since. When he arrived in Boston, in the fall of 1971, a high pressure chamber was built to his design, and grant funds were in hand.
Just before joining us in Boston, Miller made a crucial observation. He demonstrated that the same amount of hydrostatic pressure that antagonized the action of anesthetics on lipid bilayers also reversed anesthesia in newts. This demonstration provided the crucial conceptual link between then emerging in vitro studies on the effects of anesthetics on membrane structure and the physiologic phenomena of general anesthesia.
The “critical volume hypothesis” was fully described in a paper with Lever, Paton, and Smith, “Pressure Reversal of Anesthesia,” published in Nature in 1971. The hypothesis states that anesthesia occurs when the volume of a hydrophobic region, perhaps in a protein or lipid structure essential to consciousness, is caused to expand beyond a certain critical volume by the absorption of an inert substance such as an anesthetic gas. It provided a powerful thermodynamic model of anesthesia but not the molecular details. He next focused on the question of how perturbations in lipid bilayers might effect the function of excitable membrane proteins. While testing a hypothesis that anesthetics act by disordering lipids, he discovered that cholesterol played an important role in modulating anesthetic-induced disorder. He developed a powerful test of those theories of general anesthesia, based on the perturbation of phase separation of liquids within a membrane. These data pointed to regions of membranes high in cholesterol as perhaps the sites of general anesthetic action. This theme was to recur in his later studies on the acetylcholine receptor.
One interesting practical corollary of this work was that it provided a rationale for the mixing of anesthetic gases (for example, nitrogen) and nonanesthetic gases (helium) to extend the depths that deep-sea divers could attain using helium alone. Because of these studies of behavior of gases under high pressures, much of his early research at Oxford and then Harvard was funded by the Office of Naval Research. A greater understanding of decompression sickness, the high pressure neurologic syndrome, and the so-called “rapture of the deep” were immediate applications of some of Miller's work.*
Miller's research efforts constitute one of the most broadly based and systematic attacks on the unsolved problem of general anesthetic action. In a review of his work at the time of a recent National Institutes of Health special study section visit to the Harvard Anaesthesia Center of Research and Training, the report states that “Dr. Miller is probably the only individual in the world with the facilities and interest to carry out this line of experimentation.”
At Harvard, Miller was appointed an Instructor in 1971, Assistant Professor in 1973, and an Associate Professor of Pharmacology, Department of Anesthesia, in 1976. In 1983, a proposal to recommend the promotion of Miller to Professor and to assemble an endowment to support the tenured post was initiated. Dr. Henry K. Beecher, the Dorr Professor of Anaesthesia Emeritus at Harvard, had left a modest amount of unspent monies in his hospital accounts. One of his classmates at Harvard was Edward P. Mallinckrodt Jr., son of the founder of the Mallinckrodt Corporation in St. Louis. The Mallinckrodt Foundation, set up to further the medical science interest of Mr. Mallinckrodt, made a generous contribution to Harvard that, when added to contributions from the Harvard Anaesthesia Department and several friends, was sufficient to establish the Edward P. Mallinckrodt Jr. Professorship of Pharmacology in Anesthesia at the Harvard Medical School.
Meanwhile, the case was being assembled to recommend to the University that Keith Miller be appointed to the Mallinckrodt Chair. On that occasion, Professor Sir William Paton wrote:
“I have known him since 1965, when he joined the interdisciplinary group on ‘high pressure biology’ formed by Dr. E.B. Smith in Physical Chemistry and myself, and was a vital component in its success; in retrospect he has been the ablest of all…. Since then he has gone from strength to strength, and it seems to me that he has, with remarkable consistence, kept a lead in the field, varying his experimental technique according to the question to be asked, and acquiring an unrivaled diversity of experience….
“If you asked what his specific contributions had been, my (rather off-the-cuff) list would be as follows, taking account of his major contribution in all collaborative work:
(1) showing that the potency of fluorocarbon anaesthetics fitted a ‘fat solubility’ model, whereas they failed a water-solubility or ‘hydrate’ model.
(2) showing that the pressure would reverse anaesthesia in the amphibian and in the mammal, and that this reversal could be quantitatively accommodated in a ‘critical volume’ theory….
(3) discovering the effects of high pressure in the mammal, and showing that they could be antagonized by anaesthetics.
(4) developing the idea that the pressure-sensitive site mediating HPNS and that involved in anaesthesia had different physico-chemical properties.
(5) being the first to show rigorously that pressure reduces a model membrane's permeability to ions….
(6)….showing how the effect of anaesthetics on membrane fluidity depended on membrane composition,….
(7) making the first exploration of a possible consistent effect of anaesthetics (and pressure) on drug receptor function.”
Harvard University reviewed the documentation and, in 1983, Keith W. Miller became the first Edward P. Mallinckrodt Jr. Professor of Pharmacology in Anesthesia. In celebration, the Mallinckrodt Foundation funded the complete renovation and equipment of Miller's laboratory complex. It bears the title of “The Edward P. Mallinckrodt Jr. Pharmacology Laboratory of the Department of Anaesthesia” at the Massachusetts General Hospital.
Research at virtually every level represents the collaboration of excellent minds, and, in Miller's case, the number of prominent anesthesiologists who have trained with and collaborated with Miller is substantial, and includes Leonard Firestone, Barbara Dodson, Stuart Forman, and Douglas Raines.
Currently, Miller's work goes beyond elucidating the molecular mechanisms of general anesthesia and bears directly on the nature of the biology of consciousness. Miller sees anesthetic agents as tools and views the mechanisms of general and local anesthesia as camps on the way to assaulting that summit of all mysteries, the fundamental mechanisms of consciousness. Plato and Aristotle considered consciousness to be the intellect and the will that, when combined, constitute the soul. The solution to these mysteries will certainly constitute the greatest prize of all time, a cause for celebration even greater than this sesquicentennial celebration of Morton's public demonstration of ether's anesthetic qualities.
Richard J. Kitz, M.D., Henry Isaiah Dorr Professor of Anaesthesia, Faculty Dean for Clinical Affairs, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115.
*Miller KW, Paton WDM, Smith EB: Experiments on animals at ultra high pressures. Troisieme Journees Internat d'Hyperbarie et de Physiologie Subaquatique, 1972, pp 31–4.