Note: This profile was written in 2004 by Robert S. Rust, MD on the occasion of Dr. Holowach-Thurston receiving the first CNS Lifetime Achievement Award, presented at the 33rd CNS Annual Meeting in Ottawa, Ontario.
Jean Holowach-Thurston trained in medicine in her native Edmonton, Canada. She practiced pediatrics there for several years before and several more after receiving additional training in pediatrics and metabolism at Washington University, St. Louis. She returned to St. Louis in 1949 where she married Donald L. Thurston, future Chairman of Pediatrics at the St. Louis Children’s Hospital. Dr. Holowach-Thurston joined the faculty of Washington University where her initial duties included supervision of the seizure clinic and the premature infants program. She also served as consultant to the Missouri State Rheumatic Fever Program, caring for the large numbers of patients in that era who manifested serious cases with associated Sydenham chorea. From the earliest phases of her academic career, she manifested insatiable curiosity and the desire to advance understanding of the diseases of children, particularly but not exclusively neurological ones. She participated with Dr. Dennis O’Leary in the epilepsy program at Washington University.
Dr. Thurston published twenty-eight papers the first fifteen years of her career at Washington University; these included three on gastrointestinal diseases, two on hypoglycemia, nine on childhood cancer including those that arose from her early participation in the Southwestern Cancer Chemotherapy Study Group. Each of the papers that she wrote manifest the elegant formality of style that have been characteristic of her in both written and verbal communication. Each study showed excellent planning, an important hypothesis at the onset of study, and diligent follow through. They also display her capacity to observe clearly and render from her observations ambitious projects. Of particular interest was her New England Journal of Medicine paper on the association between breath holding spells and anemia—the first such observation in the medical literature. To test the view that the two entities commonly accompanied one another, she studied more than 140 cases seen at Washington University in a 27 year span and a much larger control group without breath holding.
Nine papers concerned clinical aspects of epilepsy, including studies of the efficacy of acetazolamide and ACTH. She demonstrated her penchant for enrollment of large numbers of subjects, digging back through decades of records to publish a study of 120 cases of childhood psychomotor seizures. It is, however, for her contributions to the understanding of metabolism of the developing brain that she is best known. At age 45 she joined the laboratory of Oliver H. Lowry, one of the pre-eminent brain biochemistry laboratories in the world. She devoted a three year sabbatical to becoming adept at the elegant techniques of quantitative microhistochemistry for which the laboratory was famous. She established a close and enduring research association with Lowry’s foremost colleague, Dr. David McDougal. Skills in hand, she applied herself productively to the important task of improving and validating sensitive assays designed to estimate, in very small tissue samples, the activity of several tricarboxylic cycle mitochondrial enzymes and intermediates.
Her tendency to maintain irons in several fires permitted her to develop an assay for paraldehyde and study brain penetration of this antiseizure medicine. She then turned to the study of energy metabolism of the developing brain. Her interests, both in the neurological aspects of the neonate and developmental brain chemistry, preceded by half a decade the upswing of interest by child neurologists in these topics. She was awarded and maintained for twenty years (1965-1985) ROI funding for the study of energy metabolism in the neonatal and developing brain. She extended the purview of Lowry group research into an entirely new area. Some of her studies recapitulated the Lowry group focus on sources of energy and factors that governed their depletion. Other studies were aimed at novel questions particularly pertinent to the newborn and infant. Her pioneering studies skillfully demonstrated important differences between energy metabolism in the developing and mature brain. Not content to base assumptions on just one species, she compared rat results with those in fish, frogs, and turtles. She carried out studies of fundamental importance concerning the effects of anoxia, hypoxia, and ischemia on the availability of energy substrates, the rates of their depletion and of the accumulation of potentially toxic metabolic byproducts. She demonstrated, importantly, that serum glucose was an unreliable index of brain glucose and that glucose supplementation improved outcome under anoxic conditions—a result contrary to that observed in mature brain. These results have occupied an important place in each successive edition of Volpe’s Neurology of the Newborn.
Her interest in practical applications of her bench research led her to investigate thiamine dependent enzymes of brain and liver. Her interest in improving the outcome of babies and awareness of the toxicity of many commonly employed drugs led her to investigate the degree to which vulnerability of developing brain to exhaustion of energy reserves and accumulation of toxic metabolic byproducts was influenced by administration of glucose, glycerol, insulin, aminophylline, acteyl salicylic acid, and hydrocortisone. She studied the effects of malnutrition on cerebral energy metabolism, the brain uptake and utilization of such energy sources as fructose. She had an early interest in glutamate, to which she would return in important collaborative studies with Steve Rothman. In 1971 she reported the brain penetration and effects on intermediary metabolism of this substance whose importance in neurotransmission would not be investigated for another decade.
Dr. Holowach-Thurston’s active clinical practice interested her in the question as to how long childhood epilepsies ought to be treated, since she found there was little reliable data upon which to make such decisions. A degree of anarchy existed in those days concerning decisions about stopping anti-seizure medications in children. Varied approaches ranged from discontinuation after two or four years to long-term continuation of combination therapy with phenobarbital and phenytoin. Several large studies had been published, but outcome data in these studies were scant, reflecting the difficult large-city phenomenon of patients “lost to followup”. There was little information concerning outcome by seizure type. Dr. Hollowach-Thurston’s retrospective study of 148 children, published in the New England Journal of Medicine in 1972, filled in much of the most important missing information. She demonstrated very clearly that seizure type strongly influenced recurrence risk, and identified other factors that also influenced risk for recurrence. The remarkable feature of this study was the exceptionally low number of patients “lost to follow-up”. She achieved this result because of the tenacity with which this very compulsive researcher employed reverse phone books and relentlessly pestered, often in unsavory neighborhoods, the neighbors of children who had moved away. She thereby reduced the “lost to follow-up” to negligible numbers. She was to replicate this feat in a further follow-up of this same group 11 years after the initial study, 15-23 years after anticonvulsants had been withdrawn. To her, clinical data had to be as complete and quantitative as were her enzymatic microhistochemical studies. Her results contributed to the establishment of rational therapy for childhood epilepsy and provided badly needed prognostic information that could be shared with worried patients and their families.
In the meantime, Dr. Holowach-Thurston’s laboratory, continued the important work on carbohydrate metabolism, including fructose intolerance, as well as the brain metabolic effects of diabetes and of insulin. Other investigations concerned the role of taurine in cerebral osmoregulation, factors that govern cerebral water and salt balance, and studies of cerebral and hepatic amino acid metabolism including the effects of anticonvulsants on brain and liver metabolism. She developed metabolic assays of CSF for the detection of inborn errors of metabolism and of blood for the energy state of brain.
She was among the first to investigate the possibility that valproate might confer a neuroprotective effect under hypoxic-ischemic conditions. She investigated the potential roles of carnitine, pantothenic acid, and acetylcysteine in the prevention of valproate-induced hepatic dysfunction. In the late 1980’s, she engaged in collaborative studies with Steve Rothman concerning neuroprotective effect of ketamine and the delayed neurotoxicity produced by excitatoxic amino acids. She has published, in total, nearly one hundred papers representing a breadth of interest, but a consistent and organized effort to investigate themes of particular importance.
Jean has been a devoted member of the CNS for many years and may be as well known to many members for her inimitable style of commenting on work that falls within the purview of her varied interests. She patiently but firmly coaxes younger colleagues to recognize that “all under the sun is not new” and to remember the contributions of their predecessors. Her services and excellence in encouraging young pediatricians were recognized in 1990 with the Fomon-Peters Founders Award of the Midwest Society of Pediatric Research. She challenges molecular scientists to think biochemically and asks all investigators to be certain that complex and elegant techniques are suitably adapted to the particular clinical problem at hand.
Despite the many vicissitudes to which a long career is subject, she succeeded in maintaining an active laboratory, like her mentors Lowry and MacDougal, until after her 75th birthday. A particular tribute to her personal qualities is the fact that she was able to retain the services of the same research associate, Richard Hauhart, for almost the entire four-decade history of her laboratory. The death of her beloved husband of thirty-eight years left her, late in her career, with the additional task of learning to care for his magnificent rose garden, a “third career” that worried her at the outset; but, as in all that she touches, she has also succeeded brilliantly at this.