Monday, March 02, 2015

Vernon Remembered

By: Mahlon R. DeLong, M.D., and Guy McKhann, M.D.

Editor’s Note: The world of neuroscience lost one of its pioneers when Vernon B. Mountcastle, M.D., died January 11 in Baltimore at age 96. Often referred to as “the father of neuroscience,” Mountcastle defied early skeptics by showing how cylinders of neurons, dedicated to specific tasks, work together. This month’s Cerebrum features remembrances from two colleagues influenced by Mountcastle—among the many who have gone on to make their own significant impacts in neuroscience.

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Vernon B. Mountcastle, whose career at Johns Hopkins Hospital and School of Medicine spanned more than 46 years, was known as the Jacques Cousteau of the cortex. After earning his undergraduate degree from Roanoke College in Virginia, he served in North Africa and in Europe during World War II, participating in the Normandy invasion.

Laying the Foundation

By Mahlon R. DeLong, M.D .

I first met Vernon when I was a fellow at the National Institutes of Health (NIH) in Edward Evarts’ laboratory. When I moved from the NIH to Johns Hopkins as a resident in neurology and then joined the faculty, Vernon generously provided me temporary research space in the Department of Physiology. The rich and stimulating environment and interaction with colleagues, fellows, and visiting faculty was unique. Vernon’s early advice helped with my first NIH grant application, which, almost unthinkable in the current environment, was fully funded on the first round. Collaborative studies with Apostolos Georgopoulos, and discussions with colleagues including Tom Powell, were the highlights and the beginning of one the most productive periods of my career. It was most fortunate for me to have had Vernon’s early and continued support.

Vernon, whose career at Johns Hopkins lasted more than 46 years, laid the foundations for modern neuroscience by his discovery of how brain cells in the cerebral cortex are organized. His eureka moment occurred in 1957, as he was charting the responses of individual brain cells in the sensory cortex of a cat to superficial tactile stimulation and pressure applied to the cat’s paw. As he advanced a microelectrode from the surface of the brain to the deeper layers of the cortex, he observed that brain cells responding to a particular point on the skin, with responses to either superficial stimulation or deep pressure, were stacked on top of one another in narrow, vertical columns.

The finding of columnar organization stood in stark opposition to the prevailing view that the cortex, a clearly layered structure, was organized horizontally. Some even believed each cortical layer was responsible for different and unique functions. Neuroanatomists saw no anatomical evidence for vertical columns and considered it a radical hypothesis. So controversial was the finding that his co-investigators preferred not to be coauthors on the publication. But “Modality and Topographic Properties of Single Neurons of Cat’s Somatic Sensory Cortex” is now unquestionably one of the most seminal and far-reaching publications in the field of neuroscience. His conclusion: “that the elementary pattern of organization in the cerebral cortex is a vertically oriented column or cylinder of cells.”

Although many colleagues and physiologists as well as anatomists initially viewed this conclusion with skepticism, investigators studying other regions of the cortex involved with the processing of different modalities of sensory information, confirmed Vernon’s finding. He and his colleagues continued their careful investigations, first in the anesthetized cat and then the primate, finding even further evidence of separate channels for transmission of sensory information about stimulus type and location from the periphery to the parietal cortex and for columnar organization at the cortical level.  

Although Vernon was most cited for his early work, it was his subsequent studies on the parietal cortex in the awake monkey that he considered most significant. The findings in recordings of single-cell activity in monkeys trained to perform movement tasks requiring attention to stimuli, decision making, and action in the form of movement were transformative. In his autobiography, prepared for the Society for Neuroscience in 1992, he commented that after failing to see any signs of the discriminatory process in the early stages of processing in the parietal cortex, they, “more or less in frustration,” moved the recording to the posterior parietal cortex. “What we saw that day determined my experimental life for 15 years. Neural responses to stimuli occurred only if the animal attended to them,” he said.  

Strikingly, Vernon and his colleagues observed a wide variety of motor, tactile, and visual responses in individual cells, reflecting the processes of sensory integration, attention, and decision making, observations later substantiated through painstaking studies in trained primates. Again, they found that “neurons defined by these [different] functional properties are arranged in type-specific columns.” Furthermore, they later showed that the functional properties of such neurons strikingly reflected the functions impaired following removal of the posterior parietal area in monkeys and also seen in patients with damage to this area.

Vernon’s seminal contributions over the decades led the way for the fundamental view that brain functions are distributed, with multiple modules working in concert—receiving, processing, discriminating, and acting upon their inputs.The remarkable developments in modern systems of neuroscience rest upon the fundamental view of brain organization Vernon and his colleagues first elaborated.

Certainly, Vernon will be remembered most for his scientific contributions, but those who knew, worked, or trained with him personally attest to the depth and breadth of his knowledge, the clarity of his thinking and writing, his strong work ethic, and his fairness and passion for science and discovery. This passion is reflected poignantly in his autobiography, as he reflects on the end of his investigative career in the early 1990s. It was then that he began examining the discrimination process linking the transitions from sensation to action in the cells of the motor cortex: “This was my last experience in laboratory research,” he wrote. “I was nearly brokenhearted to leave it, for I found no greater thrill in life than to make an original discovery, no matter how small.”

That passion may be a major factor in understanding his dedication and work ethic. He often finished his administrative work by 9 a.m., entered the lab, took a break for dinner at home with the family, and then returned to the lab and worked until midnight. He entered the darkened laboratory to the sound of action potentials displayed on the oscilloscope as an explorer in unexplored sacred space, the brain. As Robert LaMotte, a fellow with Mountcastle in the early studies of the parietal lobe, recalled “It was akin to going into a little submarine with him, like being the Jacques Cousteau of the cortex.”

Vernon received nearly every major award in science, including the Albert Lasker Basic Medical Research Award. The Lasker award, often considered the “American Nobel,” recognized him “for his original discoveries which illuminate the brain's ability to perceive and organize information, and to translate sensory impulses into behavior,” and as “the intellectual progenitor of the many researchers at work in neuroscience today.” David Hubel, who shared the Nobel Prize with Torsten Wiesel, for their work on the processing of visual information, said in his acceptance speech: “[Vernon’s] discovery of columns in the somatosensory cortex was surely the single most important contribution to the understanding of cerebral cortex since [Ramón y] Cajal.” Sol Snyder, commenting on the prevailing dominance of genetics and molecular biology in a 2007 interview in Hopkins Medicine magazine, stated: “The more we know of individual genes that regulate brain function, the more it becomes clear that molecular biology is just the beginning—and we need to return to the lessons of Vernon Mountcastle to put it all together.”

Snyder’s words have gained traction as we enter the era of the BRAIN Initiative, with its emphasis on linking subcellular activity, single cells, and synapses to network function and, ultimately, to complex behavior. The burgeoning field of neuroscience mourns the loss of a pioneer who contributed so greatly to its development.

 

An Unforgettable Friend

By Guy McKhann, M.D.

J ohns Hopkins and the world of neuroscience lost one of their greats last month. At age 96, Vernon still thought and acted as he had his entire scientific life. Mahlon has done a wonderful job describing Vernon’s scientific career. I will not add to that. I would, however, like to say more about Vernon as a person.

Vernon was born in Kentucky, but his family moved to Roanoke, Virginia, when he was 3. Vernon was the ultimate Virginian: proud of his ancestors, proud of his country, and proud to represent them. He was extraordinarily bright, skipping two grades in primary school, going through Roanoke College in three years, and entering Johns Hopkins Medical School at 19. He was initially overwhelmed by the Hopkins environment, surrounded by classmates from much more prestigious academic backgrounds. Furthermore, his mother had wanted him to go to a Virginia medical school, rather than be surrounded by “all those Yankees.” It wasn’t long before Vernon was more than holding his own in his new environment—an environment he never left. He went on to spend his entire career at Hopkins, with the exception of a few years in the Navy during World War ll.

Vernon intended to be a neurosurgeon and had spent a year as a surgical intern before the Navy. On his return to Hopkins, he found that things had changed. Walter Dandy, a renowned neurosurgeon, had died, and no successor had been named. The head of surgery, Alfred Blalock, had deemed that no appointments in neurosurgery would be made until a new head of neurosurgery had been found. Vernon tried another tack, applying to a Hopkins spinoff program in neurosurgery at Duke University. The Duke program was also full. On an impulse, Vernon asked if spending a year in physiology at Hopkins with Philip Bard might qualify him for a residency. Barnes Woodall, head of neurosurgery at Duke, jumped at the chance, and said that if Bard would have Vernon around for a year, he could join the Duke program. Vernon returned to Baltimore for an interview with the unsuspecting Bard. It was one of the shortest on record:

Bard: “Do you think there is a psychological factor in motion sickness?”  

Vernon: “No.”

Bard: “Come in September.”

Thus began the neurophysiology career of one of the leading neurophysiologists of all time, who was pleased to say he did his first experiment at age 28!  

To digress for a moment, I have often wondered what would have happened if Vernon had gone into neurosurgery. I think he would have been superb. He had technical gifts, as was shown in his demanding physiological experiments. He took as long as was needed and focused on specific problems. He was a great admirer of Wilder Penfield at the Montreal Neurological Institute and could have been the American equivalent.

I knew Vernon well—he recruited me to Hopkins. Hopkins had never had a neurology department; at the time neurology was a small division of medicine. Vernon, along with Bob Cooke, in pediatrics, Paul Talalay, in pharmacology, and Dave Bodian, in anatomy, lobbied for neurology becoming a department. Part of their argument was that in the previous 10 years, not a single Hopkins medical student had gone into neurology. Additionally, neurology was more than an extension of medicine; it had a basic science requiring clinical application. The final selection process came down to two candidates: Richard Johnson, and me. With the help of the superb dean at the time, Tommy Turner, two endowed professorships were obtained and Vernon recruited both of us. The development of the department to its current position as the number one department in the United States (according to U.S. News and World Report) is directly related to the direction that Dick and I provided, followed by our successors, Jack Griffin and Justin McArthur.

Vernon and I used to play tennis every Wednesday morning at 7 ‘o clock. Vernon was good—a human backboard in the sense that he hit everything back. If we played his game, good steady tennis, he would usually win. If I adapted to a game of drop shots and lobs, it was clear that Vernon didn’t consider that tennis. I usually didn’t, being somewhat ashamed of those tactics against an 80 year-old opponent. On one occasion a young man, whom I did not know, came up to me and asked: “Are you Dr. McKhann?”I said “yes,” and he went on to say that he wanted to thank me because he worked with Vernon in the lab and every time he won our tennis match, the lab was a much more peaceful place.

My other major interaction with Vernon was around the development of the Zanvyl Krieger Mind-Brain Institute. Vernon had first planted the idea with Steve Muller, president of Johns Hopkins at the time. Vernon proposed an institute that would focus on how the brain influences behavior. Muller bit and, after some start-up pains, the institute was formed. Vernon talked me into giving up the direction of the neurology department to Dick Johnson and becoming the institute’s first head. A key component of launching the institute was moving Vernon’s former colleagues there; the purpose was to make it a center of systems for neuroscience. The institute has done well despite the death of two of its stars, Ken Johnson, who succeeded me as director, and Steve Hsiao, who was its scientific director. The present director, Ed Connor, is continuing Vernon’s considerable legacy.

I cannot finish without remarking about Vernon’s remarkable wife, Nancy. She is 92 and still going strong. Nancy balanced Vernon’s life, seeing to the kids, taking in foreign graduates and visitors, teaching school, and also playing tennis into her late 80s—all this with Virginian charm. Nancy is a steel magnolia if there ever was one, and I mean that in a most positive way.

This has been a difficult piece to write for me, so soon after Vernon’s death. I say goodbye to a first-rate scientist, human being, and friend.

 



About Cerebrum

 
Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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