Dr. Charles Kennedy studied chemistry at Princeton prior to attending medical school at the University of Rochester, from
which he graduated in 1945. During his internship at Yale-New Haven, where he served as an Instructor in pathology, Malcolm Carpenter fostered his interest in neuroanatomy. Two years of military service a Veterans Hospital were followed by five months of training in child psychiatry and eighteen in pediatrics at the Children’s Hospital of Buffalo. While there, Mitchell Rubin helped to arouse his interest in clinical research. Between 1951 and 1954 Kennedy completed fellowships in physiology and neurology at the University of Pennsylvania. Malcolm Carpenter made Dr. Kennedy an excellent neuroanatomist, an attainment that in time would figure importantly not only to Dr. Kennedy, but for much of the work that the Kety-Sokoloff group at the NIMH would undertake upon his joining them.
The faculty of Penn’s world famous programs in physiological biochemistry included, among others Otto Meyerhof, Julius Comroe, Carl Schmidt (until their respective departures to the NIMH in 1951 and 1953), and the brilliant young biochemist, Seymour Kety. Kety had recently published the famous nitrous oxide method that would open the whole field of cerebral blood flow and metabolic study of conscious humans. Dr. Kennedy first came into contact there with another young and scientifically ambitious Research Fellow in the Physiology Department, Louis Sokoloff. Both came to this laboratory to learn to apply the Kety method to neurological investigation.
Dr. Kennedy wished to adapt the method to the study of children and as Assistant Professor of Pediatrics at CHOP was given laboratory space. Sokoloff joined Kennedy in this effort and recalls that Kennedy “worked brilliantly and successfully to achieve his goal.” Kennedy in turn joined Sokoloff in a study of the effects of adult higher cortical functions in adults on cerebral metabolism. This collaborative work resulted in the first of what would be many pioneering team efforts and also established a firm friendship that has now lasted for nearly 60 years. Sokoloff’s study was published in 1955. Kennedy’s report demonstrating the efficacy and safety of the nitrous oxide method in children was published in 1957 and included the first normative values for cerebral blood flow and metabolism in children. For this work Kennedy also developed and published a micro method for measurement of nitrous oxide in blood.
Kennedy and Sokoloff also collaborated in completing the first study of interictal cerebral blood flow in children with epilepsy. Kennedy shared his background in psychiatry with both Kety and Sokoloff, both of whose dissatisfaction with psychoanalytic theory played an important role in their motivation to investigate the neurochemical basis of behavior. Kennedy had received additional impetus in this direction from psychiatrist and famous medical educator, John Romano, whose studies of the biochemical basis of most delirium would further undermine psychoanalytical theory.
As Kennedy’s promising career in neuroscience began to blossom, Houston Merritt encouraged him to interrupt this work long enough to obtain an additional year of clinical training. Kennedy was among the first three trainees of the first formally sanctioned program for training in child neurology in America, under Sid Carter, and became the first individual whose formal training qualified him for subsequent recognition with the awarding of formal boards in neurology and child neurology. While at Columbia he became interested in childhood optic neuritis and multiple sclerosis, upon which subject he published his first clinical papers. In 1959 Kennedy was named first Chief of the newly established Division of Neurology at the Children’s Hospital of Philadelphia as well as Director of Child Neurology. During the decade that he held this position he often traveled by train to Columbia to participate in Carter’s patient rounds.
Although he continued studies of cerebral metabolism, the pace of that aspect of his research career slowed given clinical duties that on the other hand contributed to his sophistication as clinician and clinical scientist. He published the first studies of blood flow, metabolism and brain growth in children with mental retardation. He also published a large series of patients with SSPE, papers concerning behavioral manifestations of brain damage, clinical aspects of encephalitis. Other papers concerned childhood venous sinus thrombosis, nemaline myopathy, myelomeningocele, and encephalopathic hemorrhagic pancreatitis. Kennedy studied the predictive value of Apgar sores for infant mortality and of neurological examination for ensuing child development. Maintaining his Columbia connection, he published with Vivian Shih and Bud Rowland a study of homocystinuria (1965). Kennedy attracted promising young individuals to his program, individuals who became the first entries in what would become a long list and distinguished CHOP child neurology trainees.
Inevitably, Kennedy gradually expanded his concentration on basic research with an important pioneering study of changes in regional blood flow and metabolism in both foetal and neonatal monkeys subjected either to hypoxia or asphyxia. The opportunity to do these studies came because Bill Windle, Chief of the Laboratory of Perinatal Physiology at the NINDS wished to provide this additional information about the animals upon which he had already done pioneering work. He invited Kennedy, Sokoloff, and Kety to spend a month at the animal colony in San Juan, Puerto Rico. The researcher brought their families as well. This resulted in further development of a social bond between all three researchers and their families that would also last decades. Kennedy then took a sabbatical year in order to learn the deoxyglucose methods that Kety and Sokoloff had developed to measure regional blood flow in brains of conscious animals.
Kennedy was a quick study and this highly successful year led Kennedy to decide to accept appointment as Professor of Pediatrics at Georgetown with the commitment that he could spend half or more of his time at the Kety- Sokoloff lab at the NIH. Peter Berman assumed the Chair at CHOP, where (as the saying goes) the rest is history.
For Kennedy, this was the beginning of more than two decades (1967-1990) of intensive and highly successful collaborative experimentation concerning matters relevant to the neurological diseases of children, particularly those afflicting the neonate. He participated with his anatomical and technical expertise in projects concerning individuals of all ages, but strongly influenced the group’s expanding concentration on developing brain. Kennedy developed the venerable beagle pup model that has been used subsequently in countless studies of hypoxic-ischemic stress and developing brain and participated in other canine studies resulting overall in the production of a remarkable documentation of the various changes in cerebral blood flow and metabolism that occur from birth to adulthood that the laboratory produced within the next decade. These studies, a model of group effort in intellectual and technical collaboration, thus resulted in the first systematic data on such developmental changes in experimental animals. Kennedy employed and helped to develop other animal models, notably the rat.
The studies of immature animals helped to explain and resolve seeming discrepancies between data the group had accumulated demonstrating decline in bloodflow of normal human brain after peak whole-brain flows at six years of age and data obtained by other researchers in slices of brains of animals at various developmental ages. In a landmark paper, Kennedy showed that regional aspects of brain development must be taken into consideration in order to explain whole-brain data. He was the first to demonstrate that bloodflow (and hence metabolism) is high in developing white matter with ensuing decline in the course of maturation. He related these changes to high metabolic demands for myelin synthesis. The classic body of work on metabolism of developing beagle puppy brain resulted in five additional classic papers in 1972 (first author in most), including his most highly cited paper as first author, summarizing a wealth of data on regional blood flow and metabolism.
Kennedy made additional prescient observations concerning the role that immaturity of vascular autoregulation in developing brain might play in vulnerability to injury, a suggestion that would occupy the attentions of neuroscientists for the next thirty years – including three studies that Kennedy himself would organize with Sokoloff. By the end of the 1970s, Kennedy joined with a distinguished list of co-authors (Kennedy respectively second and third) in publishing two masterful papers summarizing the antipyrine (1079 citations) and the perfected 14C deoxyglucose (4478 citations!) methods for estimation of global and regional cerebral blood flow and metabolism. The largest part of all ensuing understanding of brain blood flow and metabolism would be based upon these studies. The approach itself, refined over decades after Kety’s initial adaptation of the Fick principal, led in time to the development of PET scan techniques that would carry these such work from the laboratory to the bedside.
Three Kennedy papers on the effects of hyperoxia on brain blood flow, growth, and metabolism were early important contributions to the effort to protect brains from incurring the injury to which retinas were known to be vulnerable. The concern over hyperoxic retinal injury to neonates had been among the stimuli that led to the establishment of the NIMH research laboratories in the first place. Kennedy participated in many other projects as a critical member of the team from planning through execution to interpretation. He was coauthor of 13 seminal papers on functional mapping of visual pathways (1st author in 5), two on regional mapping of normal l mature monkey brain awake (1st author 1) and six while asleep (1st author 2). He was first author of a similar study of normal neonatal monkey brain and an attempt to provide metabolic evidence for plasticity of developing brain and another study of effects of hydrocephalus on regional metabolism.
Kennedy was first author in two of three important studies of functional mapping of motor activity. He was coauthor of a paper mapping the hibernating brain (as a model for neuroprotection), and of a study extending normative regional date to rat brain and another (as 1st author) to neonatal and mature – the former since constituting a very important model for neonatal brain injury. He also coauthored studies of regional metabolism/blood flow in epilepsy including effects of ACDs (3), thyroid disease (3), hypoxemia (1), hypoglycemia (8; 1st author of 1), amphetamine (1), epinephrine (1), morphine (1), physostigmine (1), x-irradiation (1). Of 10 additional important methodological summaries/ refinements/validations he coauthored he was 1st author in two.
It is impossible within the allotted space to do justice to his remaining achievements as scientist. Perhaps it is most fitting to allow Dr. Sokoloff to summarize Kennedy’s importance:
“Charles was present and a major figure in our team throughout the development and applications of our Lab’s highly regarded deoxyglucose method for measuring local cerebral glucose utilization. In fact, he was my principal and essential collaborator who contributed very significantly to the success of our lab’s research. He not only provided the necessary neuroanatomical and neurophysiological expertise needed for the design and interpretation of the results of these studies, but be oversaw, coordinated, trained, and directly supervised the research activities of the numerous post-doc fellows….He very effectively carried out these functions, largely because of the nature of his character. Charles is the most genuinely modest, humble, often self-effacing and sometimes self-sacrificing, dedicated, unselfish, kind, and empathetic person I have known in many years in science. These qualities were recognized and admired by generations of fellows who worked with him in our lab. He is regarded and respected by all as a great teacher and outstanding gentleman, I am proud to be able to recognize him as a collaborator and friend.”
As clinician, Kennedy taught at Georgetown. Having come to child neurology long before any neonatal curriculum was available, he was able on the basis of his own work to bring this information to those he taught. He published a few additional clinical reports on genetic disease and on coma and in time authored an account of the life of Duchenne and another of the career of Louis Sokoloff. Honors have included guest lectureships and visiting professorships nationally and internationally, Presidency of the Philadelphia Pediatric Society, Directorship of the International Society for Blood Flow and Metabolism, and membership on the editorial boards of three prestigious journals. His personal life has been enriched by a long and fulfilling marriage and by his lifelong love of music – Dr. Kennedy is a fine pianist. His personal distillation of the qualities that it is most important to instill into young physicians becoming child neurologists is “Humility, curiosity, and sensitivity to feeling.”