Siegel, J.M.

Dept. Psychiatry and Brain Research Institute, UCLA and Neurobiol. Res. (151A3), VA GLAHCS, North Hills, CA 91343

Nathaniel Kleitman, who died on August 13, 1999 at the age of 104, can be properly described as "the father of modern sleep research." His claim on this title stems from both his scholarly integration of the work in the field and his own research. His 1939 compendium of prior work on sleep and wakefulness, revised in 1963 (13), includes thoughts on sleep ranging from Aristotle and other ancient thinkers to 20^th century pioneers such as Piéron, Hess, Nauta and Kleitman’s contemporaries. The explosive recent growth of the field guarantees that this will be the last such comprehensive, research oriented integration of the literature in sleep research. In the introduction to the 1939 edition, Kleitman apologizes that his reading abilities are "limited to French, German, Italian and Russian" (and English). However, despite this "handicap" he critically integrates 4337 references covering sleep, circadian rhythms, sleep disorders, hibernation and theories of sleep function.

Kleitman’s research forms the foundation for many of the areas of current sleep research. His studies of sleep-wake and temperature rhythms in the isolation of Mammoth cave were a key event in the history of human circadian rhythm research. He carried out some of the first scientific studies of drug effects on sleep. His discovery with Eugene Aserinsky of REM sleep (4) is the key event in 20^th century sleep research and led directly to the growth of the field in the last half of the 20^th century. His work identified the developmental course of the human sleep cycle and highlighted the importance of ultradian rhythms. Indeed in what I believe was Dr. Kleitman’s last publication he emphasized the importance of ultradian rhythms, which he felt were more fundamental to sleep than the REM-nonREM cycle (14).

Dr. Kleitman pursued his research with inventiveness and determination. His "apparatus for determining and for recording motility and rectal temperature during sleep" (page 83 (13)) is a prime example, monitoring and timing bed movement and incorporating what can now be described as a primitive polygraph to produce a continuous readout of motor activity and achieve measurement that only recently became practical with microelectronic technology. His choice of the constant environmental conditions of Mammoth cave for his circadian rhythm studies necessitated his devising and incorporating traps to prevent rats from climbing into bed with the sleepers. This certainly would have been a confounding variable!

An exceptional rigor and conservatism in interpreting the results characterized all of his research. Eugene Aserinsky, Kleitman’s graduate student who died in 1998, relates the story of Kleitman’s skepticism about his discovery of REM sleep. After the initial finding made on Aserinsky’s son, Kleitman insisted that his own daughter serve as a subject. Aserinsky surmises that this demand was to assure Kleitman that no fakery was involved in the presence of rapid eye movements while what appeared to be a waking EEG was present (3).

Fig. 1. Nathaniel Kleitman in undated photograph.

Dr. Kleitman was blessed with an exceptional intellect until the very end of his life. Well into his 80’s and 90’s I would often see him at the UCLA biomedical library, at research meetings in Los Angeles and at the annual APSS meeting, usually in the company of his daughter Ester. I was delighted to have the opportunity to organize a special symposium honoring Kleitman on his 100th birthday at the APSS (sleep) meeting in Nashville in 1995. It was with some trepidation that I asked him if he would be willing to talk about his career at the opening plenary session, attended by over 2,000 researchers and clinicians. I was comforted by the thought that Bill Dement who chaired the session would handle any problems that arose with kindness and tact. But Bill’s sensitivity was not required. Kleitman gave a clear and moving presentation, explaining his fascination with the early work in sleep, the obstacles he faced, particularly the perception that sleep was not a proper subject for serious science and his amazement at the growth and impact of the field. Following the talk, attendees snapped up the specially reprinted edition of Sleep and Wakefulness and pursued him for autographs throughout the meeting.

Fig. 2. Kleitman monitors sleep of assistant Bruce Richardson in Mammoth cave.

This memorial volume incorporates reminiscences and biographic information by William Dement regarding his long and warm relationship with his mentor. Don Bliwise relates Kleitman’s eagerness to help as a subject in his studies of sleep in the elderly and his feisty independence and resourcefulness. Eiland and Lyamin of my group present the first studies of neuronal activity during reptilian sleep and use it to address the question of sleep evolution, an issue carefully considered by Kleitman in his book. Mircea Steriade relates his work with intracellular recording of neurons during sleep to the issue of active vs. passive theories of sleep that were a central aspect of Kleitman’s work. Borbely considers issues of sleep homeostasis in the context of Kleitman’s pioneering sleep deprivation studies. McGinty, Szymusiak and their collaborators consider the role of the hypothalamus and thermoregulatory mechanisms in sleep control, representing the modern development of the work of Hess, critically discussed by Kleitman. Sakai presents a state of the art review of what we now know about the REM sleep state. In keeping with Kleitman’s focus on motor activity during sleep, Pompeiano presents his work on the role of locus coeruleus in muscle tone control across the sleep cycle. Kubin reviews work on cholinergic regulation of REM sleep. Sanford et al. present work on the control of phasic events during REM sleep. Harper presents recent work on autonomic control during sleep and its relation to sudden infant

Fig. 3. Kleitman (center-right) and assistant Bruce Richardson (center) emerge from Mammoth cave on July 6, 1938.

death. Robert Moore et al. present the first description of the hypocretin neurons in humans, a system that has recently been implicated in REM sleep control and in narcolepsy. Mignot reviews the history of narcolepsy research, highlighting Kleitman as one of the early doubters of the psychosomatic theory of narcolepsy. Tononi and Cirelli discuss recent research investigating the role of REM and nonREM sleep in neural plasticity. Roth and Roehrs discuss recent work on drug effects on sleep connecting these studies to Kleitman’s pioneering investigations of the pharmacology of sleep. Doran et al. discuss modern studies of sleep deprivation, building on Kleitman’s pioneering studies in this area. Mahowald and Schenck review the important clinical phenomenon of sleep state dissociation and its relation to the REM sleep behavior disorder and narcolepsy. And finally Carskadon et al. review the interaction of sleep loss and developmental changes, an area that is leading to changes in schedules for adolescents worldwide so as to maximize their nighttime sleep and daytime alertness. The breath of this work and commonality with Kleitman’s work is testament to his scientific vision and the extent to which all sleep researchers are in his debt.

It is fitting that this tribute to Kleitman appears in Archives of Italian Biology. It was in Archives that

Fig. 4. Kleitman serves as subject in sleep study.

one of the first sleep deprivation studies in animals, performed by Manacéine, appeared. The Archives published key work by the Scheibels (20; 21) and by Sprague (22) on the reticular formation and by Jankowska et al. (11) identifying brainstem mechanisms suppressing muscle tone. Classic studies by Villablanca on sleep in the athalamic and diencephalic animal (23; 24), and by Bremer on control of the EEG (5) appeared in Archives. The definitive lesion study on REM sleep control by Carli and Zanchetti (6) appeared in Archives as did Jouvet’s classic monograph on REM sleep (12). Pompeiano and his colleagues including Morrison and Hoshino (10; 15-19) published classic work on cholinergic control of REM sleep and the control of PGO spikes. Finally, it was in Archives that some of the key studies of the phylogeny of sleep by Allison and colleagues (1; 2) and by Rechtschaffen, Flanigan and others (7-9) appeared. The current volume continues this tradition and represents the continuation of some of the many areas of research first explored and codified by Nathaniel Kleitman. Dr. Kleitman has left a great legacy to sleep research.

Fig. 5. From left to right, Michel Jouvet, William Dement, Nathaniel Kleitman and Eugene Aserinsky, after their symposium on the discovery of REM sleep presented at the Nashville meeting of the Associated Professional Sleep Societies on June 1, 1995. The symposium commemorated the 100th birthday of Nathaniel Kleitman in April of 1995.

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