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The Life and Science of Patrick David Wall, 1925-2001

Patrick D. Wall, a pillar of pain science and medicine, died of cancer in his home in London on August 8, 2001. He was 76. I dare say that all members of IASP know the name P.D. Wall, and that most can place him as a coauthor with Ronald Melzack of the famous "Gate Control" theory of pain. The theory's impact is probably known to most, and its gist to many, although the specific electrophysiological data upon which it was based are probably familiar to relatively few. As a scientist, Pat was more than just a creator of data; he was a source of ideas and an arbiter of direction for our entire field. He was a modern-day prophet.

Pat Wall was born in Nottingham, England, in 1925. After qualifying in medicine at Oxford University he served for a short time in post-war Europe treating refugees and survivors of the Holocaust. He then moved to the United States in 1948 for what would be a sojourn of nearly 20 years. Early work at Yale University and later at the University of Chicago imprinted him with the conviction that lower level phenomena (such as nociception) are accessible at the level of the neuron, while those at a higher level (such as pain) require a conscious brain. Of the Yale effort to understand functions of the frontal lobes in monkeys, for example, Pat quipped that "there was little chance of progress when our first act in preparing to observe was to anesthetize the animal." In 1953 he moved to the remarkable group of Warren McCulloch at the Massachusetts Institute of Technology (MIT) where the gate theory was born. Finally, in 1967 he returned to England, to University College London (UCL), where he built a superlative research group. There he became known, in a phrase that rather pleased him, as "Mr. Pain". Pat's main base remained in London for the remainder of his career, although he enjoyed regular research interludes elsewhere, sometimes at the American University in Beirut, but particularly at the Hebrew University of Jerusalem, where he maintained an active laboratory from 1972.

Although Pat distained "the establishment", always favoring individuals, best mavericks, he in fact did a great deal within the framework of organized science. He was John Bonica's scientific staff officer in the creation of the International Association for the Study of Pain. He founded IASP's journal, Pain, today number one in anesthesiology and high in the neuroscience citation ratings. He edited, together with Ron Melzack, THE Textbook of Pain, currently in its fourth edition, authored a series of popular books on pain (most notably The Puzzle of Pain [1973] and Pain: The Science of Suffering [1999]) , made frequent appearances on radio and television, and was always a sought-after speaker at scientific gatherings. Pat had a message, and all of these vehicles helped him to get it across. Even more important, however, is the fact that his lab was a magnet for students, postdocs, and sabbatical visitors. Many of these went on to populate and to found centers of pain research around the world. The word spread.

Part of Pat's success as a communicator was due to his tendency to do battle with prominent figures who took opposing positions. The battle lines were clearly drawn between classical specificity theory, the easily teachable doctrine that pain follows a simple path from nociceptor, along specific ascending pathways, to pain centers in the cortex, and the new, and more complex gate control vision that highlights convergence, modulation, and a distributed processing network encompassing much of the brain. These confrontations, in person and in print, were always full of acid humor, and they won the gladiators considerable attention. In doing so, they also shed light on important scientific issues that might otherwise have been buried in dusty pages of academia. Was public combativeness a conscious device? Pat never denied it. But it also reflected a deeply felt contempt for a set of ideas that Pat felt did not emanate from reason or data, and that ultimately did a powerful disservice to pain patients . Pat was a fighter, like Bonica, but in a different ring. When Pat spoke of specificity theory as being "19th-century science," he meant it.

In his personal bearing, Pat was reserved and dispassionate. He married three times, but had no children. I never met his first wife, Betty, but have heard her described as a quiet, warm person, interested in British history, and an accomplished amateur painter. His second wife, Vera, a Jerusalemite and an accomplished enamel artist, is a mix of passionate gypsy and warm Jewish mother. Some of Pat's happiest hours were spent holding forth in a parlor full of artists, architects, and intellectuals in their two homes, one, appropriately, on the Street of the Prophets in Jerusalem, and the other in London. But the marriage was not to last. After a long period of withdrawal, Pat married Mary McLellan, a fellow of the arts who lives in London. No gypsy, Mary-she's an angel on earth.

Pat's essence was his science. And this was always focused on creative discovery rather than technical pizzazz . His object was peripheral nerve and spinal cord. The work for which he became famous began at MIT with the identification of a gradient of electrophysiological properties to match the recently defined laminar anatomy of the dorsal horn. He was the first to apply current source density analysis to the spinal cord, and to identify the special modulatory properties of the substantia gelatinosa. During this period he also invented primary afferent terminal excitability testing as a way, along with the dorsal root potential and the dorsal root reflex, of monitoring interactions among signals entering the spinal cord. These studies formed the experimental basis of the gate control theory. Pat interpreted his work on afferent modulation as reflecting presynaptic inhibition, a radical concept that was roundly scorned by the academic deities of the time. One of these, Sir John Eccles, only a few years later won a Nobel prize based largely on presynaptic inhibition. Other discoveries of the MIT period include "wind-up" of dorsal horn neurons on repeated C-fiber stimulation and the clinical treatment modalities of TENS and dorsal column stimulation.

His stream of discoveries continued in London and Jerusalem. Highlights include the control of convergence properties of deep dorsal horn neurons by descending pathways, and a whole series of findings concerning the plasticity of somatosensory maps in the thalamus, dorsal column nuclei, and dorsal horn following lesions of input pathways. The work on map plasticity was a major turning point in Pat's thinking. Up until then control and gating mostly meant short-term modulation of nociceptive processing, as when one strokes bruised skin or is briefly distracted from pain. But map reorganization reflected enduring neuroplasticity, measured in months, not minutes. Might it be relevant to chronic neuropathic pain? As recently as the 1970s neuropathic pain was a complete mystery. Some attempted to understand it in term of the gate control concept. In postherpetic neuralgia, for example, there is a preferential loss of large diameter Ab afferents that should spell pain according to the gate theory. However, this is the exception, not the rule.

Neuroplasticity, which was center stage in the 1970s, revolved around axonal sprouting and the establishment of new synaptic connections, particularly in development. Sprouting had also been claimed in the adult spinal cord following rhizotomy. But the Wall group found that maps were readjusting too quickly for sprouting to be the explanation, and that remapping was induced by peripheral nerve lesions that do not evoke the massive degeneration that triggers sprouting. This led to a new concept: that existing anatomical connectivity in the adult brain is broader than the physiology that is reflected in receptive fields. Receptive fields, Pat proposed, are sculpted from this excess, but not necessarily by inhibition. The idea was that many synapses in the brain are "relatively ineffective" or "silent" synapses. Rapid map plasticity results from functional strengthening of pre-existing, but weak, connections. Similar events in the domain of sensory quality could underlie chronic pain. Pat's idea of dynamic modulation of intrinsic synaptic strength, in contrast to pre- or postsynaptic inhibition, at first was widely ignored. A decade later, with the discovery of NMDA-type glutamate receptors and the advent of computational network modeling, this concept became a central dogma of neuroscience.

Wall and colleagues discovered many additional neuroplastic mechanisms associated with nerve injury and rhizotomy that form the basis for our current understanding of chronic pain. High on the list were the discoveries of spontaneous ectopic impulse discharge and abnormal sensitivities (mechanosensitivity, adrenosensitivity) in nerve-end neuromas, and later in axotomized dorsal root ganglion neurons. These changes in the "phenotype" of injured sensory neurons were extended to cytochemical markers (e.g., peptide neurotransmitters) and to structural properties of central projections. Signals transported in the axoplasmic flow (notably neurotrophins) were implicated as a key link between axonal injury and phenotypic change. In parallel, Pat realized the importance of having animal models of chronic pain. This insight led to the rhizotomy model of root avulsion pain and the neuroma model of phantom pain/anesthesia dolorosa.

One of the hallmarks of Pat's research after leaving MIT was an intense interest in chronic pain as seen in the clinic. Like Bonica, he was convinced that chronic pain is a disease in its own right, much different from the acute pain evoked in healthy subjects by brief noxious stimuli. Gate control posits that activation of myelinated Ab fibers, e.g., by light touch, should suppress pain. But in the event of injuries such as burns and some neuropathies, weak stimuli are pain provoking. Such "allodynia" used to be explained in terms of sensitized nociceptors, and it still is for elevated response to thermal stimuli. But for tactile allodynia, i.e., everyday tenderness, the data are simply not there. By the late 1980s the evidence for Ab touch-evoked pain was becoming widely accepted. Wall's London group provided the mechanism: "central sensitization.".

After his official retirement from UCL, Pat continued collaborating with colleagues, including the group in Jerusalem, and undertook a fascinating new series of experiments with new students in space provided at St. Thomas'. This work has not had much impact yet, but it is quite brilliant, including evidence for intrinsic resonance in the spinal cord, and an entirely new mechanism of afferent gating based on the control of spike invasion into afferent terminals. When I saw Pat at a conference in Istanbul in late June 2001, only 5 weeks before his death, he sat on the edge of his chair excitedly showing me new data along these lines.

The fact that much everyday pain results from activity in Ab afferents appeared to be the final nail in the coffin of specificity theory. However, Pat sometimes expressed the nagging suspicion that what seemed to be widespread understanding and acceptance of his gating/plasticity scheme by the mid 1990s, might in fact be so much dust. For example, new data from noninvasive brain imaging (especially PET and fMRI), which he felt so clearly vindicated his vision of a complex, integrated pain network, appeared to him instead to be giving rise to a new phrenology. He was proud of the special issue of Pain put out in his honor (Supplement 6, 1999), filled with original contributions by his former students. However, he was uneasy about the classical air of many of the papers. Most of all, he was concerned that molecular neurobiology and the knockout mouse was once again focusing attention on the peripheral nociceptor, as if activity of the nociceptor were the sole determinant of nociception. "Has no one been listening?"

Although Pat's bench research mostly focused on nerve and spinal cord , his thoughts ranged much further. Particular interests were acupuncture, anticipation, and the placebo effect. He frequently spoke of pain not as a sensory input signal, like vision or hearing, but as a "need state" more akin to hunger and thirst. Another favorite theme was that in nociceptive processing the brain is not asking "what's out there," but rather "what can be done in response." Pat felt that these earlier formulations, admittedly fuzzy, were becoming clearer with new attempts at placing pain "in context.", as he tried to do in his presentation at the 9th IASP World Congress in Vienna (1999). The great triumph of 20th-century biology was the unification of three problem areas-heredity, development, and evolution-within the framework of a single mechanism, the DNA molecule. The relationship of this grand synthesis to pain was very much on Pat's mind in the past year or two. Biological questions are increasingly being formulated at the molecular level. Nor did Pat feel this is unwise if the aim is to create a better aspirin. But he strongly felt that this trend misses the point of pain. Whereas heredity is clearly a matter of molecules, as is development (largely) and evolution (partly), pain manifestly is not. Pain is an unpleasant sensory and emotional experience, something that can exist only in a conscious brain. Pain, per se, does not exist at the level of the molecule. The study of pain must not lose sight of mind.

Pat, we have lots of writers, editors, lecturers and experimenters, but who can step into your shoes as prophet ?

Marshall Devor
Department of Cell and Animal Biology
Institute of Life Sciences
Hebrew University of Jerusalem
Jerusalem, Israel
[Reprinted, with permission of IASP, from the IASP Newsletter Dec.2001. A longer version of this essay appeared in Pain 94(2001) 125-129]

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