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Scientist Emeritus: David C. Klein, Ph.D.

Positions at NIH

  • 1969: Fellow, Laboratory of Biomedical Sciences, DIR, NICHD
  • 1973: Member, Laboratory of Developmental Neurobiology, DIR, NICHD
  • 1977-2014: Head, Section on Neuroendocrinology, DIR, NICHD
  • 2015-present: Scientist Emeritus, DIR, NICHD 


The son of Jewish immigrants who came to the United States as young children, David C. Klein was raised in New Rochelle, New York, and graduated from high school in 1957. He attended Cornell University, where he met his future wife, Gail Levinson.

After graduating with his B.A. in 1962, Dr. Klein worked in the Department of Physical Biology at the Rockefeller Institute, where he was first exposed to X-ray crystallography and structural biology. In 1964, he received his doctorate from Rice University for his work on the control of circulating calcium by thyrocalcitonin, then just discovered, under Roy V. Talmage. During postdoctoral work at the University of Rochester with Larry G. Raisz, Dr. Klein discovered that prostaglandins promote bone resorption. He then initiated independent work on the pineal gland, realizing that it provided an ideal model for developmental studies on the mechanisms that control tissue-specific gene expression.

This work on the pineal gland continued when Dr. Klein came to NICHD in 1969, as a fellow, and as he continued his career with NICHD. During his career, Dr. Klein established productive collaborations with experts in a broad range of disciplines, including functional neuroanatomy, molecular biology, pharmacology, electrophysiology, histology, and structural biology. The advances resulting from these collaborations enriched and invigorated the field of pineal research. Later, he expanded his research on the pineal gland to study how gene expression is regulated by a complex circadian system. Dr. Klein has contributed more than 400 publications to biomedical literature.

Among Dr. Klein’s seminal contributions and discoveries are the following:

  • The role of norepinephrine (PMID: 4915470). Dr. Klein discovered that norepinephrine regulates acetyltransferase activity in the pineal gland, and the effects of this primary messenger were mimicked by the intracellular messenger, cyclic AMP. Subsequently, it was discovered that cyclic AMP acted through mechanisms that control two processes: 1) expression of the N-acetyltransferase gene, and 2) “turnoff,” or the destruction of the enzyme by proteosomal proteolysis.
  • Daily rhythms in pineal metabolism (PMID: 4915470 and PMID: 5050487). Dr. Klein’s work showed that enzyme activity responsible for serotonin acetylation followed a 24-hour rhythmic pattern, characterized by a rapid 100-fold increase in activity at night in the dark (Figure 1). Disrupting the darkness by turning lights on at night caused the enzyme to rapidly decrease. The strong day/night rhythm persisted in total darkness, a characteristic of true circadian rhythms.
  • Melatonin synthesis (PMID: 9238858). Melatonin is synthesized from serotonin by two enzymatic steps: 1) the formation of N-acetylation serotonin from serotonin; and 2) O-methylation of N-acetylserotonin to form melatonin. Although most work on melatonin at the time focused on step 2, Dr. Klein’s work confirmed step 1 as the primary control point, a finding that redirected the field.
  • Action of melatonin (PMID: 401360). Using the neonatal pituitary gland, Dr. Klein found that melatonin could block the Gonadotropin-Releasing Hormone (GnRH)-induced release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This and other research confirmed that melatonin was pro-gonadotrophic in some animals. It was a conserved output of the circadian system in all vertebrates, used to tell time.
  • Neural regulation (PMID: 4595289 and PMID: 487129). The large day/night change in N-acetyltransferase activity served as a reporter, or a biological “light bulb,” in a series of studies to determine the neural pathway involved in controlling the pineal gland. Earlier work had shown that sympathetic nerves transmitted signals to the pineal gland and identified suprachiasmatic nucleus (SCN) of the hypothalamus as the site of a circadian clock that drove this rhythm. Dr. Klein’s team discovered that circadian signals are generated in the SCN and transmitted to the pineal gland via a hardwired route. The signals then passed through the periventricular nucleus, to the spinal cord, and then to the sympathetic nervous system, specifically to cells that innervated the pineal gland and released norepinephrine into the pineal extracellular space. Based on this and other work, the SCN is referred to as the “Mind’s Clock” for its role in controlling circadian rhythms.
  • A pineal/retinal-specific N-acetyltransferase (PMID: 6469990). Dr. Klein’s work showed that arylalkylamine N-acetyltransferase (AANAT), a previously undescribed enzyme, preferentially acetylated serotonin and related amines. Based on this evidence, the enzyme received the identification number E.C. and earned the moniker “The Timezyme.”
  • Pineal/retinal evolution and AANAT (PMID: 16687276). Discovery of the presence of the retinal protein S-antigen in the pineal gland suggested a common link between the pineal gland and retina, and was eventually found to represent a group of genes that are expressed only in these two tissues. One group is dedicated to photoneural signal transduction in the retina. It is expressed strongly in the retina, but only to a varying degree in the pineal gland. The other group, melatonin synthesis genes including AANAT, are very strongly expressed in all vertebrate pineal glands, but not in the retina. Based on these observations, Dr. Klein hypothesized that a single ancestral cell existed early in the evolution of vertebrates that detected light and made melatonin.
  • Cloning of AANAT and sequence analysis (PMID: 7502081). The cloning of AANAT opened a new door in the study of melatonin synthesis, making it possible to obtain the RNA and protein sequence of the enzyme in any species, and to study how AANAT mRNA transcription was regulated. Dr. Klein’s team also benefited from the sequencing AANAT in that it: revealed cyclic AMP-dependent phosphorylase sites—binding partners for 14-3-3—located at the C- and N-terminal ends of the molecule; allowed for obtaining large amounts of protein for a range of studies, including X-ray crystallography; and enabled comparative studies on AANAT in vertebrates, revealing marked conservation of structure and universality.
  • The AANAT/14-3-3 complex and its function (PMID: 11336675 and PMID: 17164235). Through cloning and sequencing of AANAT, Dr. Klein and colleagues observed that AANAT eluted in two peaks of activity. They hypothesized that the larger fraction reflected the formation of a complex with another protein, and the smaller was free enzyme that played a key role in future research. This work resulted in the finding that phosphorylated AANAT and 14-3-3 form a complex (Figure 2 external link). Later work revealed that binding partner was a member of the 14-3-3 proteins family, a widely distributed family of binding partners that interact with many enzymes.
  • RNA sequencing advances (PMID: 19103603). Dr. Klein’s team was able to identify changes in long non-coding RNAs and in micro RNAs in the rat. Later, they extended the effort to include other vertebrates, as well as pineal mRNA and retinal mRNA studies. These results were summarized in a 2020 report of an online resource database ( that contains expression of tens of thousands of transcripts in the pineal gland and retina, with samples taken during the day and night.
  • Expression of AANAT and other transcripts (PMID: 30347410). During Dr. Klein’s career, as techniques to study specific mRNA transcripts changed remarkably, so too did the scope of his interest in mRNA. By 2009, DNA chip technology made it possible to detect daily changes in hundreds of mRNAs in the rodent pineal gland. In 2015, Dr. Klein’s team used sequencing to demonstrate that essentially all day/night changes in transcript levels were due to neural input (Figure 3). The team then combined single cell isolation with sequencing to determine the cell specificity of a gene product, and to develop defining profiles of each cell type. As a result, in 2018, they established profiles of nine cell types (Figure 4), allowing for a clear picture of the genes that characterize each cell type, and the location of specific gene products in one or two cell types, which can be used to generate metabolic scheme unique to specific cells.

Selected Publications

Mays, J. C., Kelly, M. C., Coon, S. L., Holtzclaw, L., Rath, M. F., Kelley, M. W., & Klein, D.C. (2018). Single-cell RNA sequencing of the mammalian pineal gland identifies two pinealocyte subtypes and cell type-specific daily patterns of gene expression. PLoS One, 13(10), e0205883. PMID: 30347410

Bailey, M. J., Coon, S. L., Carter, D. A., Humphries, A., Kim, J. S., Shi, Q., Gaildrat, P., Morin, F., Ganguly, S., Hogenesch, J. B., Weller, J. L., Rath, M. F., Møller, M., Baler, R., Sugden, D., Rangel, Z. G., Munson, P. J., & Klein, D. C. (2009). Night/day changes in pineal expression of >600 genes: Central role of adrenergic/cAMP signaling. The Journal of Biological Chemistry, 284(12), 7606-7622. PMID: 19103603

Klein, D. C. (2007). Arylalkylamine N-acetyltransferase: "The Timezyme" The Journal of Biological Chemistry, 282(7), 4233-4237. PMID: 17164235

Klein, D.C. (2006). Evolution of the vertebrate pineal gland: The AANAT hypothesis. Chronobiology international, 23(1-2), 5-20. PMID: 16687276

Gothilf, Y., Toyama, R., Coon, S. L., Du, S. J., Dawid, I. B., & Klein, D. C. (2002). Pineal-specific expression of green fluorescent protein under the control of the serotonin-N-acetyltransferase gene regulatory regions in transgenic zebrafish. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 225(3), 241-249. PMID: 12412006

Obsil, T., Ghirlando, R., Klein, D. C., Ganguly, S., & Dyda, F. (2001). Crystal structure of the 14-3-3: Serotonin N-Acetyltransferase Complex: A role for scaffolding in enzyme regulation. Cell, 105(2), 257-267. PMID: 11336675

Klein, D. C., Coon, S. L., Roseboom, P. H., Weller, J. L., Bernard, M., Gastel, J. A., Zatz, M., Iuvone, M., Rodriquez, I. R., Begay, V., Falcon, J., Cahill, G., Cassone, V. M., & Baler, R. (1997). The melatonin rhythm generating enzyme: Molecular regulation of serotonin N-acetyltransferase in the pineal gland. Recent Progress in Hormone Research, 52, 307-357. PMID: 9238858

Coon, S. L., Roseboom, P. H., Baler, R., Weller, J. L., Namboodiri, M. A. A., Koonin, E. V. & Klein, D. C. (1995). Pineal serotonin N-acetyltransferase: Expression cloning and molecular analysis. Science, 270(5242), 1681-1683. PMID: 7502081

Klein, D. C., Moore, R. Y., & Reppert, S.M. (Eds.). (1991). Suprachiasmatic Nucleus: The Mind's Clock. Oxford University Press.

Voisin, P., Namboodiri, M. A., & Klein, D. C. (1984). Arylamine N-acetyltransferase and arylalkylamine N-acetyltransferase in the mammalian pineal gland. The Journal of Biological Chemistry, 259(17), 10913-10918. PMID: 6469990

Klein, D. C., & Moore, R. Y. (1979). Pineal N-acetyltransferase and hydroxyindole-O-methyltransferase: Control by the retinohypothalamic tract and the suprachiasmatic nucleus. Brain Research, 174(2), 245-262. PMID: 487129

Martin, J. E., Engel, J. N., & Klein, D. C. (1977). Inhibition of the in vitro pituitary response to luteinizing hormone-releasing hormone by melatonin, serotonin, and 5-methoxytryptamine. Endocrinology, 100(3), 675-680. PMID: 401360

Klein, D. C., & Moore, R. Y. (1974). Visual pathways and the central neural control of a circadian rhythm in pineal serotonin N-acetyltransferase activity. Brain Research, 71(1), 17-33. PMID: 4595289

Klein, D. C., & Weller, J. L. (1972). Rapid light-induced decrease in pineal serotonin N-acetyltransferase activity. Science, 177(4048), 532-533. PMID: 5050487

Klein, D. C., & Weller, J. L. (1970). Indole metabolism in the pineal gland: A circadian rhythm in N-acetyltransferase. Science, 169(3950), 1093-1095. PMID: 4915470

Klein, D. C., & Raisz, L.G. (1970). Prostaglandins: Stimulation of bone resorption in tissue culture. Endocrinology, 86(6), 1436-1440. PMID: 4315103

Access Dr. Klein’s full list of publications on the National Library of Medicine’s PubMed® database.

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