Editors' Note: Alan Light, University of Utah, Salt Lake City, US, remembers the life and work of a pioneering pain researcher. We invite you to share your memories of Ed Perl by posting a comment below.
Dr. Edward R. Perl, nociceptor pioneer and champion of the specificity theory of pain, and a founding member and first president of the Society for Neuroscience, passed away July 15, 2014.
Perl, with Paul Richards Burgess and Paul Bessou, documented in the late 1960s the existence of unique A-delta and C-fiber “nociceptors” by using single unit recordings. “Our routine of testing by gentle mechanical stimulation yielded no activity. After some minutes of fruitless trial, one of us, and we cannot remember whom, picked up a tissue forceps and pinched the skin in the middle of the nerve's receptive field. This evoked a burst of impulses. We looked at each other across the experimental table, both recognizing what we may have seen, and then systematically explored the unit's responsiveness,” said Perl in The History of Neuroscience in Autobiography (Volume 3, Ed. Larry R. Squire). So began the modern era of discovery, characterization, and, ultimately, understanding of the cellular and molecular nature of nociceptors. Perl, along with Burgess and Bessou, documented the important characteristics of A and C nociceptors, including their differential responses to noxious temperatures, and the property of “sensitization,” in which the nociceptors become much more responsive following damage to the tissues they innervate. During this time, Perl coined the name “polymodal nociceptor” to describe C nociceptors that responded to noxious mechanical, thermal, and chemical stimuli.
In the early 1970s, Perl, with Burgess Christensen, went on to show that these nociceptors activated specific neurons in the marginal zone and substantia gelatinosa of the spinal cord in the cat and, as shown later with Takao Kumazawa, in the monkey as well. Later in the 1980s, with Christopher Honda and Siegfried Mense, Perl showed that these neurons activated neurons in specific regions of the thalamus.
During the later 1970s and 1980s, Perl, Alan Light, Dan Trevino, and Miklós Réthelyi, as well as Yasuo Sugiura and Chong Lam Lee, established the anatomical substrates for these pathways by using intracellular labeling of physiologically defined A and C nociceptor primary afferent neurons and similarly identified neurons in the superficial dorsal horn. To determine if these “nociceptors” were, in fact, responsible for the sensation of pain, Perl, with Frithjof Konietzny, Trevino, Light, and Herbert Hensel, further showed that activation of specific nociceptors led to the sensation of pain in humans. These experiments clearly demonstrated the existence of a “labeled line” for pain from nociceptors in the periphery to the thalamus in the brain.
In the early 1990s, Perl, with Jun Sato, Daniel Bossut, and Virginia Shea, showed how damage to the sympathetic-adrenergic system could enhance nociceptor signaling and thus how sympathetically related pain states could be established.
More recently, Perl, with Timothy Grudt, Adam Hantman, Yan Lu, and Jihong Zheng, turned his attention to how the substantia gelatinosa is organized to receive and modulate input from peripheral A- and C-fibers.
Perl received the Bristol-Myers Squibb Award for Distinguished Research on Pain in 1991 and the Ralph W. Gerard Prize in Neuroscience in 1998. He was elected to the American Academy of Arts and Sciences in 1992. In 2000, Perl endowed the University of North Carolina (UNC)-Perl Prize to be given to investigators who have made significant contributions to neuroscience through outstanding or seminal insights. Four of the winners of this prize have gone on to win Nobel Prizes.
Early life and training
Edward Roy Perl was born in 1926 in Chicago, Illinois, US. His parents, John and Blanche Perl, were natives of Hungary and Czechoslovakia, respectively. Perl attended college at the University of Chicago where he enjoyed physics and engineering but was convinced by his physician father to go into the field of medicine. He began a medical training program in the United States Navy Officer Training program as a medical trainee in 1945 at the University of Illinois School of Medicine, graduating with a medical degree in four years, in 1949, at the age of 22. It was during this time that he developed his interest in neuroscience, and met and worked with many of the top scientists in the country in this area of research.
Dr. Perl’s first Science paper, published the same year he obtained his medical degree, was not on pain systems, but on a device to measure cardiac volume in humans. This project became the foundation for today’s impedance cardiography, an important tool in cardiovascular diagnostics. However, he had already developed an interest in neuroscience through his experience in Warren McCulloch’s lab, in which he also coincidently met Walter Pitts, Jerome Lettvin, and Patrick Wall, one of the originators of the gate theory of pain some 17 years later.
“McCulloch and his coterie of associates, Pitts, Lettvin, and Wall, spent most of their time in the unit's library discussing and considering various theoretical approaches to the functional organization of the nervous system. That was heady stuff. I did not understand much of it. However, the gravity of their postulations and the complexity of the situations they were considering were impressive,” wrote Perl in The History of Neuroscience in Autobiography.
In 1948, Perl served as a clerk at Harvard Medical School, Boston, US, where he met Derek Denny-Brown, who influenced him to pursue a career in neurophysiology.
After obtaining his medical degree, Perl did a fellowship with Philip Bard and Vernon Mountcastle at Johns Hopkins, Baltimore, US, where Perl became a neuroscientist and interested in C-afferent fibers, a preoccupation that would encompass the rest of his scientific career.
Perl entered active duty as a Navy physician from 1952-1954, becoming part of a research group that included David Rioch, Robert Galambos, Michael Fuortes, Walle Nauta, and David Whitlock.
A career in neuroscience
In 1954 Perl took his first faculty position at the State University of New York, College of Medicine in Syracuse (now SUNY Upstate Medical University), US. He left for the University of Utah, Salt Lake City, US, in 1957 because of the efforts of Carlton Hunt, who had formed one of the strongest neuroscience-focused departments of physiology in the US. At the University of Utah, Perl collaborated with David Whitlock and published three very influential papers on the spinothalamic pathways and the properties of thalamic neurons that responded to activation of those pathways.
In 1962, Perl began a lifelong connection with European neuroscientists with a year in Toulouse, France (he went to France speaking no French). During this time, his interactions with Paul Bessou, Denise Albe-Fessard, Pierre Buse, Jean-Marie Besson, and Hungarians Janos Szetagothai and Miklós Réthelyi not only added stature to his research efforts, but also aided his research efforts in technical ways, and imbued a lively atmosphere to his laboratory in Utah and North Carolina, since return visits by these dignitaries were frequent for years to come.
In 1963, upon returning to Utah, Perl began his research on C-fibers in earnest, armed with some of the tools necessary to study them. He modified these tools and added to them to create methods that allowed him to study large numbers of physiologically characterized neurons with Paul Richards Burgess and Paul Bessou, and in doing so revolutionized our concept of what nociceptors were and how they behaved in both cats and monkeys.
In 1969, asked by Ralph Gerard to do so, Perl wrote the initial bylaws for a scientific organization that later was called “The Society for Neuroscience.” Perl was elected president of this organization by the founding group of 20, but he chose to take the title of “acting president” because he felt that what was needed was a scientific society, devoted to neuroscience, that was as democratic as possible—one with a leader elected by a representative membership. In 1970, the Society elected Vernon Mountcastle as the first elected Society for Neuroscience president, and the first meeting was held in 1971. Today, the Society has nearly 40,000 members in more than 90 countries and 130 chapters worldwide.
In 1971, Perl moved to Chapel Hill, North Carolina, US, to become chair of the department of physiology at the University of North Carolina School of Medicine for the next 18 years.
In 1989, he resigned as chair following a conversation with a friend. “I asked my mentor and friend, Vernon Mountcastle, over a beer at a meeting in Stockholm on a sunny Swedish day what he thought about resigning the position as chair. He looked at me without a smile and said, ‘It would be the happiest day of your life,’ ” Perl wrote in The History of Neuroscience in Autobiography.
Throughout his outstanding career of over 43 years at the University of North Carolina, Perl continued to solve difficult problems with sometimes controversial results.
Outside of the lab, he enjoyed fine wine, fly fishing in remote areas, sailing along North Carolina’s outer banks, and his wife and family. He has taught many of us a most important lesson, which is how his autobiography ends: “One does not know what tomorrow will bring, but today I still look forward to the pleasure that comes from a successful experiment or that of an evening's sail, the excitement of seeing a trout or salmon rise to a fly, or of the smile of a grandchild. I close this on the way to ask Marjorie [Perl’s wife] for a dinner rendezvous.”
Alan R. Light, PhD, did his postdoctoral work under Perl at the University of North Carolina School of Medicine, Chapel Hill, US; became a faculty member in Perl’s department in 1978; and collaborated with Perl at UNC until 2003. Light is now a professor in the departments of anesthesiology, and neurobiology and anatomy at the University of Utah, Salt Lake City, US.
Burgess PR, Perl ER.
J Physiol. 1967 Jun;190(3):541-62.
Bessou P, Perl ER.
J Neurophysiol. 1969 Nov; 32(6):1025-43.
Christensen BN, Perl ER
J Neurophysiol. 1970 Mar; 33(2):293-307.
Kumazawa T, Perl ER.
J Comp Neurol. 1978 Feb 1;177(3):417-34.
Light AR, Perl ER.
J Comp Neurol. 1979 Jul 15;186(2):133-50.
Light AR, Trevino DL, Perl ER.
J Comp Neurol. 1979 Jul 15;186(2):151-71.
Perl, Edward. "Edward R. Perl." The History of Neuroscience in Autobiography, Volume 3. Ed. Larry R. Squire. San Diego: Academic Press, 2001. pp. 366-413.