John Leonora

John Leonora (January 30, 1928 - February 17, 2006) was an endocrinologist and faculty member at Loma Linda University. His research focused on the role of hypothalamic "factors" for indirectly controlling the metabolism of such avascular tissues as dental enamel, dentin, and the Islands of Langerhans (pancreas).

John Leonora, 2005

Biography

John Leonora, son of Joseph Leonora and Carmela Folise Leonora, was born in Milwaukee, Wisconsin, soon after his parents arrived as immigrants from Sicily.

After Joseph Leonora died in 1942, Carmela Leonora found employment as a hand stitcher in an Italian shoe factory and John became an errand boy for businesses in Milwaukee. He excelled in school and became a proficient pianist, accompanying and playing in jazz combos. He was an active member of the Italian club at Lincoln High School. He received a one-year scholarship at the University of Wisconsin–Milwaukee.

Upon receiving his B.S. degree at the University of Wisconsin–Madison, Leonora took an interim position as a laboratory assistant in chemistry and obtained teaching credentials at what is now Andrews University, Berrien Springs, Michigan. There he met Johanna Mae Zwemer, who was working toward a secretarial degree. They married in 1952. Leonora had returned to Madison and the University of Wisconsin. There he and his wife lived while he completed his Ph.D., obtained a federal fellowship, and embarked on his career as an endocrinologist.

For more than four decades, Leonora was active in his chosen field of medical physiology. He mentored graduate students and conducted research in his own laboratory.

Career

Research contributions

Based on his doctoral studies and subsequent research fellowship, Leonora initially intended to devote his career to the investigation of gonadotropic hormones. One day he received a telephone call from Ralph R. Steinman, a dental colleague who had been studying the flow of dentinal fluid in rats from the odontoblasts in the dental pulp through the dentin using an intraperitoneal injection of the fluorescent dye, acriflavine hydrochloride. He found that in the teeth of rats fed a cariogenic diet the flow of dentinal fluid was markedly reduced. He wondered if some systemic mechanism was involved in this impairment and so decided to contact Leonora, as an endocrinologist.[1]

This was the beginning of a decades-long collaborative journey. Leonora first suggested that none of the recognized hormones were plausible candidates for regulating dentinal flow transport (DFT), but that the hypothalamus might well be an alternative hormonal source. Quickly they found that infusing rats with a crude extract from rabbit hypothalami triggered increased DFT activity. This, however, raised the question whether the hypothalamic factor had a direct effect on the teeth or rather had an indirect effect characteristic of other hypothalamic hormones.

Assuming that the hypothalamic factor was mediated through one of the major salivary glands, they found that this factor was biologically active when administered to rats with intact parotid glands but was wholly ineffective in rats that had the parotid glands removed. There was no involvement of the other salivary glands. They concluded that the direct regulation of DFT was therefore secreted by the parotid glands and this endocrine function was controlled by the hypothalamus.

The next step was to isolate the purified parotid hormone from porcine glands, determine its amino acid structure and then confirm its stimulation of DFT. Then the hypothalamic parotid hormone releasing factor was partially purified but not completed because of the rejection of a research grant application. While the research was thus diverted it persisted in other directions.

First, an antibody to the porcine parotid hormone was produced, isolated, and used for a radioimmunoassay of the parotid hormone. Later an ELISA method (enzyme linked immunoadsorbent assay) was developed for measuring the parotid hormone titer in biological fluids.

Then the research focused on the mechanism by which dietary sucrose suppressed the DFT. Initial studies suggested that the sucrose suppressed the secretion of the parotid hormone. Further studies showed that the sucrose effect occurred indirectly by inhibiting secretion of the hypothalamic parotid hormone releasing factor. Then it was found that the sucrose effect could be effectively reversed by the infusion of the compound carbamyl phosphate through the internal carotid artery. This confirmed that the site of action was within the central nervous system—namely the hypothalamus.

Intact rats fed carbamyl phosphate along with a cariogenic diet showed a highly significant reduction in caries. Carbamyl phosphate, however, was ineffective in parotidectomized rats. Therefore, an intact hypothalamic-parotid gland endocrine axis was found to be necessary for the effectiveness of carbamyl phosphate.

The next question was what physiological factors normally stimulate the secretion of the parotid hormone? Feeding pigs a standard pig chow proved to effectively stimulate parotid hormone secretion along with the copious secretion of saliva. Surprisingly, pigs fed nonnutritive substances and exposed to auditory, olfactory and visual cues salivated profusely, but these cues did not change the fasting level of the parotid hormone. This demonstrated that, although the endocrine and exocrine functions of the parotid glands occur concurrently, they must be controlled by different mechanisms. The nutritive composition thus proved to be critical for the secretion of the parotid hormone. Apparently nutritive substrates activate neural stimuli going to the hypothalamus, which in turn activates the hypothalamic-parotid gland endocrine axis that then stimulates the dentinal fluid transport mechanism.

At this juncture a group of investigators at the University of Oulu Dental School, Oulu, Finland, Tjaderhane, L. et al., (1994) discovered that the parotid hormone not only regulates the flow of dentinal fluid but also is involved in the formation of dentin—dentinogenesis. They also found that a high sucrose diet in young rats suppressed primary dentinogenesis. The injection of carbamyl phosphate significantly reversed the effect of sucrose—but only in intact rats. Further, carbamyl phosphate prevented the atrophy of the parotid glands associated with the ingestion of sucrose.

Subsequent research cloned the porcine cDNAs that code for the parotid hormone gene. The amino acids encoded by these cDNAs agreed with the amino acid sequence of the hormone isolated from the porcine parotid glands. In addition, a commercially available synthetic parotid hormone was found to have an activity indistinguishable from the isolated parotid hormone or the gene-expressed hormone.

Meanwhile, it was discovered that the acinar cells of the parotid glands were apparently the source of the parotid hormone.

Preliminary research suggested the parotid hormone not only regulates dental structures but also influences insulin secretion by the pancreas.

These systemic effects have yet to be followed up. As Leonora stated in an undated letter, "I anticipate finding receptors [for the parotid hormone] in the odontoblasts in teeth, osteocytes in bone matrix, Islets of Langerhans…"

Academic recognition

1976: Walter E. Macpherson Society, Research Award
1980: Walter E. Macpherson Society, Basic Science Teacher Award
1980: Sigma Xi Research Merit Award
1988: Walter E. Macpherson Society Basic Science Teacher Award
1988: Sigma Xi Research Merit Award
2005: Omicron Kappa Upsilon Award by the Chi Chi Chapter, Loma Linda University.

References

Dentinal Fluid Transport. Clyde Dentinal Fluid Transport. Loma Linda University Press. 2005.