Clifford J. Woolf, M.D., Ph.D.

n a corner of the Boston Public Garden stands a tall neogothic monument commemorating the demonstration at Massachusetts General Hospital (MGH) on October 16, 1846, by William T.G. Morton, that inhaling ether produces a reversible state of insensibility during surgery. The monument carries a quotation from the Book of Revelations: “Neither shall there be any more pain.” Unfortunately that dream was not realized in 1846 and remains a dream to this day. Clifford J. Woolf, M.D., Ph.D., has dedicated his professional career to dissecting out the physiological and biochemical mechanisms of pain sensation in what he passionately maintains is the essential first step in promoting a rational basis for the effective management of pain. He has done this with persistence, flair, imagination and innovation.

A native of South Africa, Dr. Woolf became a medical student in Johannesburg in the early 1970s at the height of the apartheid government’s power. Dr. Woolf was immediately confronted with the limitations of an empirical approach to analgesia. He undertook studies of transcutaneous electrical nerve stimulation and completed M.B., Ch.B. and Ph.D. degrees at the University of Witwatersrand, Johannesburg, South Africa. Following training in medicine, he emigrated to London with his wife, Fredia, where he held medical and research posts at Middlesex Hospital and later University College London (UCL). There Dr. Woolf was fortunate to study under the tutelage of Professor Patrick D. Wall, the undisputable giant of the pain field and the co-discoverer of the spinal gate control theory.

In this innovative laboratory, Dr. Woolf went on to discover an important phenomenon that has become known as “central sensitization.”¹ Dr. Woolf worked hard to show that the phenomenon could be detected in dorsal horn neurons,² involved activation of N-methyl-D-aspartate receptors, was reduced by opiates and contributed to tactile allodynia and secondary hyperalgesia.³ Nevertheless he continued to face skepticism about its clinical significance, which stimulated him to collaborate in clinical trials on the relative merits of morphine analgesia given before or after surgery in an attempt to prevent or pre-empt central sensitization.⁴ It now seems difficult to believe, but at that time, there was enormous resistance from anesthesiologists and surgeons to administering an analgesic until a patient complained of severe pain. It is one of Dr. Woolf’s major achievements that many now recognize that treating pain early is both scientifically valid and ethically essential. He eventually became a Professor of Neurobiology at UCL.

In 1997 I recruited Dr. Woolf from a chilly laboratory in London to Boston where he became the first incumbent of the Richard J. Kitz Chair of Anesthesia Research at Harvard Medical School and Director of the Neural Plasticity Research Group in the Department of Anesthesia and Critical Care at MGH. The attraction was twofold: an opportunity to retool his laboratory in a much more molecular biological direction and to be part of MGH’s ongoing commitment to translating science from bench to bedside.

During the time that Dr. Woolf has been at MGH, he has consolidated his new laboratory into one of the major centers of pain research in the United States. His research team has exploited subtractive hybridization and microarrays to reveal that hundreds of genes are regulated in pain-related conditions in dorsal root ganglion and dorsal horn neurons and has shown that some of these genes are likely to be the targets for completely new classes of analgesics.⁵ His laboratory has participated in the cloning of a novel nociceptor sensory neuron-specific sodium channel,⁶ defined the intracellular signaling pathways and ion channel/receptors that mediate central sensitization⁷ and revealed that cyclo-oxygenase 2 is induced in the spinal cord after peripheral inflammation and that this is a major target for the analgesic action of cyclo-oxygenase inhibitors.⁸ Complementing this, he has expanded the scope of his research to include an analysis of why the central nervous system fails to regenerate and how neurons survive or die after injury.^9-10

Perhaps echoing the synaptic mechanisms underlying central sensitization, Dr. Woolf runs his laboratory as a facilitator, maximizing and increasing the efficacy of the activities of his talented, highly motivated and loyal research staff, including Laboratory Manager Andrew Allchorne, Gary J. Brenner, M.D., Ph.D., Jason A. Campagna, M.D., Ph.D., Michael Costigan, Ph.D., Joachim Scholz, M.D., and Tarek Samad, Ph.D.

It is for his extraordinary productivity and leadership in the field of pain research that Clifford J. Woolf, M.D., Ph.D., will be awarded the 2004 Award for Excellence in Research immediately preceding the Emery A. Rovenstine Memorial Lecture on Monday, October 25, at the Las Vegas Hilton.


References:

1. Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983; 306:686-688.

2. Cook AJ, Woolf CJ, Wall PD, McMahon SB. Dynamic receptive field plasticity in rat spinal cord dorsal horn following C primary afferent input. Nature. 1987; 325:151-153.

3. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain.1991; 44:293-299.

4. Richmond CE, Bromley LM, Woolf CJ. Preoperative morphine pre-empts postoperative pain. Lancet. 1993; 342:73-75.

5. Costigan M, Befort K, Karchewski L, et al. Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci. 2002; 3:16.

6. Tate S, Benn S, Hick C, et al. Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons. Nat Neurosci. 1998; 1:653-655.

7. Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci. 1999; 2:1114-1149.

8. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001; 410:471-475.

9. Neumann S, Woolf CJ. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron. 1999; 23:83-91.

10. Benn S, Perrelet D, Kato A, et al. Hsp27 upregulation and phosphorylation is required for injured sensory and motor neuron survival. Neuron. 2002; 36:45.

Warren M. Zapol, M.D., is Anesthetist-in-Chief, Massachusetts General Hospital and Reginald Jenney Professor of Anesthesia, Harvard Medical School, Boston, Massachusetts.