he stated purpose of the ASA Award for Excellence in Research is to recognize an individual who has made “original, mature and sustained contributions to the extension and advancement of knowledge in anesthesiology” and whose work has “… altered understanding of the science of anesthesiology.”

Nicholas P. Franks, Ph.D.

The mechanism of anesthetic action is the longstanding pharmacological enigma at the core of anesthetic knowledge, and no one has done more to unravel this mystery than Nicholas P. Franks, Ph.D., Professor of Biophysics and Anaesthetics at Imperial College and Head of Biophysics at the Blackett Laboratory in London, England. Dr. Franks’ discoveries and insights have revolutionized research on mechanisms of anesthetic action and have created an intellectual framework that has facilitated remarkable advances in understanding how anesthetics work.

Dr. Franks’ formal career in science began with an undergraduate education in physics at Brunel University, London, followed by Ph.D. training in biophysics with the Nobel laureate Maurice Wilkins, Ph.D., at King’s College, also in London. At King’s College, Dr. Franks met William R. Lieb, Ph.D. (recently deceased), with whom he would forge a lifelong collaboration that would focus on molecular mechanisms of general anesthetic action.

When Dr. Franks began to study mechanisms of anesthetic action in the 1970s, it was widely agreed that general anesthetics acted by disrupting the structural or dynamic properties of biological membranes. Dr. Franks’ and Dr. Lieb’s initial neutron diffraction studies showed that clinical concentrations of general anesthetics had minimal effects on membrane structure and that these effects could not explain anesthetic action.^1,2 They postulated that anesthetics must act at amiphilic sites on proteins and not on the lipid bilayer.^3,4 These results were vigorously attacked by the protagonists of the lipid perturbation theory and would not begin to be accepted for nearly a decade.

He and Dr. Lieb next undertook a series of studies examining anesthetic effects on the water-soluble protein, luciferase, in fireflies. They showed that general anesthetics inhibited luciferase activity in proportion to their octanol/water partition coefficient; thus the Meyer-Overton correlation could be entirely explained by anesthetic interactions with a protein rather than by effects on the lipid components of the membrane.⁴ In a landmark paper (recently republished in Anesthesiology as a “classic citation”), they went on to show that anesthetic inhibition of luciferase was competitive with respect to the substrate luciferin, indicating that anesthetics bind to specific sites on luciferase.⁵ The demonstration of a specific anesthetic binding site that obeyed the Meyer-Overton rule immediately suggested that anesthetics might act by binding to discrete protein-binding sites on neuronal proteins. In 1998, Dr. Franks and colleagues published a high-resolution X-ray crystallographic structure of firefly luciferase with an anesthetic molecule in the luciferin-binding site, confirming the conclusions they had drawn from functional studies in the early 1980s.⁶

In an effort to identify the specific neuronal protein targets that he had postulated, Dr. Franks soon made another seminal discovery, identifying a novel neuronal potassium channel (I_Kanest) in the pond snail that is selectively activated by inhalational general anesthetics.⁷ Subsequently mammalian homologs of I_Kanest, including TREK and TASK, also have been shown to be activated by inhalational anesthetics.^{8, 9} Recent studies have shown that “knock-out” of TREK-1 in mice results in a substantial reduction in sensitivity to inhalational anesthetics,¹⁰ indicating that Dr. Franks’ initial finding identified an important protein target of inhalational anesthetic action.

Another important discovery was the finding that a variety of inhalational¹¹ and intravenous^{12, 13} anesthetics act enantioselectively on ion channels. This work led to the use of enantioselectivity as a powerful criterion for identifying relevant molecular targets of anesthesia. The demonstration that anesthetics act in an enantioselective manner also dealt a final blow to nonspecific lipid perturbation theories, since anesthetic enantiomers are equally soluble in lipid membranes yet have markedly different anesthetic potency in animals.

In 1994, Dr. Franks and Dr. Lieb wrote the most important and best-cited review in the field of molecular mechanisms of anesthetics.¹⁴ This review identified the principal targets for general anesthetics and set a roadmap for subsequent work on anesthetic mechanisms. Dr. Franks’ own contributions in the ensuing years have led the way in investigating the “anesthetic-sensitive superfamily” of receptors, including the nicotinic acetylcholine receptor,^{15, 16} glycine receptor¹⁷ and GABA_A receptor.¹⁸ Dr. Franks also has shown that the anesthetic xenon acts on the NMDA-type glutamate receptor rather than on the anesthetic-sensitive superfamily of ion channels.¹⁹

Recently Dr. Franks has directed his work to the next steps in understanding anesthetic action. First, he has used X-ray crystallography to define the molecular details of anesthetic binding to specific protein sites.^{6, 20} In collaboration with Mervyn Maze, M.B., Ch.B., Imperial College, London, he also has begun to look at the systems-level actions of anesthetics. They have recently shown that a specific hypothalamic nucleus, the tuberomammilary nucleus (known to play an important role in natural sleep), may be critical in anesthetic-induced loss of consciousness.²¹ The idea that general anesthetics may produce their primary effects via actions at specific anatomical sites in the brain will doubtless be an important focus of Dr. Franks’ subsequent work.

In concert with his fervent pursuit of research, he has a well-developed sense of humility and humor and engages in an eclectic range of extra-vocational activities. He is a great enthusiast for rugby and other team sports. His vigorous support for his beloved English national teams is tempered only by the allegiance of his wife, Ange, and his sons Peter and Pablo, to Spain. Dr. Franks also is an avid fly fisherman and can often be seen musing and casting in equal measure on the rivers of south Wales.

Throughout his career Dr. Nick Franks has passionately engaged himself in a quest to understand how general anesthetics work. He has married skepticism with creativity, marshalling an array of physical and biological techniques to repeatedly make groundbreaking discoveries. When his ideas were scorned, he persevered using logic and a compelling “quiet charisma” to convince the skeptics. His presentations at international meetings on “cellular and molecular mechanisms of anesthetic action” were always a tour de force, never failing to galvanize his audience. He has actively engaged the community of anesthesiologist-scientists and has been a frequent speaker at the ASA Annual Meeting and an associate editor of Anesthesiology. In pursuing his quest, Dr. Franks has made staggering contributions to our understanding of anesthetic mechanisms and has been the dominant figure in this field for 30 years. I can imagine no one more deserving of the ASA Award for Excellence in Research for 2006 than Nicholas P. Franks, Ph.D.


References:
1. Franks N, Lieb W. The structure of lipid bilayers and the effects of general anaesthetics. An x-ray and neutron diffraction study. J Mol Biol. 1979; 133:469-500.
2. Franks NP. Is membrane expansion relevant to anaesthesia? Nature. 1981; 292:248-251.
3. Franks NP, Lieb WR. Where do general anaesthetics act? Nature. 1978; 274:339-342.
4. Franks NP, Lieb WR. Molecular mechanisms of general anaesthesia. Nature. 1982; 300:487-493.
5. Franks NP, Lieb WR. Do general anaesthetics act by competitive binding to specific receptors? Nature. 1984; 310:599-601.
6. Franks NP, Jenkins A, Conti E, Lieb WR, Brick P. Structural basis for the inhibition of firefly luciferase by a general anesthetic. Biophys J. 1998; 75:2205-2211.
7. Franks NP, Lieb WR. Volatile general anaesthetics activate a novel neuronal K+ current. Nature. 1988; 333:662-664.
8. Patel AJ, Honore E, Lesage F, et al. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci. 1999; 2:422-426.
9. Gruss M, Bushell TJ, Bright DP, et al. Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol. 2004; 65:443-452.
10. Heurteaux C, Guy N, Laigle C, et al. TREK-1, a K+ channel involved in neuroprotection and general anesthesia. EMBO J. 2004; 23:2684-2695.
11. Franks NP, Lieb WR. Stereospecific effects of inhalational general anesthetic optical isomers on nerve ion channels. Science. 1991; 254:427-430.
12. Tomlin SL, Jenkins A, Lieb WR, Franks NP. Stereoselective effects of etomidate optical isomers on gamma-aminobutyric acid type A receptors and animals. Anesthesiology. 1998; 88:708-717.
13. Tomlin SL, Jenkins A, Lieb WR, Franks NP. Preparation of barbiturate optical isomers and their effects on GABA_A receptors. Anesthesiology. 1999; 90:1714-1722.
14. Franks NP, Lieb WR. Molecular and cellular mechanisms of general anesthesia. Nature. 1994; 367:607-614.
15. McKenzie D, Franks NP, Lieb WR. Actions of general anaesthetics on a neuronal nicotinic acetylcholine receptor in isolated identified neurones of lymnaea stagnalis. Br J Pharmacol. 1995; 115:275-282.
16. Violet JM, Downie DL, Nakisa RC, Lieb WR, Franks NP. Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology. 1997; 86:866-874.
17. Downie DL, Hall AC, Lieb WR, Franks NP. Effects of inhalational general anaesthetics on native glycine receptors in rat medullary neurons and recombinant glycine receptors in Xenopus oocytes. Br J Pharmacol. 1996; 118:493-502.
18. Hall AC, Lieb WR, Franks NP. Stereoselective and non-stereoselective actions of isoflurane on the GABA_A receptor. Br J Pharmacol. 1994; 112:906-910.
19. Franks NP, Dickinson R, de Sousa SL, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature. 1998; 396:324.
20. Bhattacharya AA, Curry S, Franks NP. Binding of the general anesthetics propofol and halothane to human serum albumin. High-resolution crystal structures. J Biol Chem. 2000; 275:38731-38738.
21. Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia is mediated by GABA_A receptors in an endogenous sleep pathway. Nat Neurosci. 2002; 5:979-984.

Alex S. Evers, M.D., is Henry E. Mallinckrodt Professor and Chair, Department of Anesthesiology, and Professor of Internal Medicine and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri.