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Stumpf, Walter E |
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Degrees
Dr.med. 1952
Humboldt-University , Berlin
1957 Specialty in Neurology and Psychiatry
Ph.D. Pharmacology 1967
University of Chicago , Chicago
Awards
- Examination for Medical Doctor all grades A (summa cum laude), 1952
- Berlin Laboratories Fellowship, 1968-69
- Robert-Feulgen-Lecture, Histochemische Gesellschaft, Gargellen, 1982
- Bissendorf Lecture, European Anatomical Society, Antwerpen, 1987
- Dr.rer.biol.hum.h.c., University of Ulm, Germany, 1987
- Pfizer Traveling Fellow, Clin. Res. Inst., Montreal, 1989
- Humboldt Senior Scientist Award, Ulm, 1989
- Monbushou Visiting Professor, Shinshu University, Matsumoto, 1990
Studied medicine at the University of Leipzig (1946-1950) and Berlin (1950-1952). Medical residency at the Charité-Hospital in Berlin (1952-1957) and the Department of Neurology and Psychiatry of the University of Marburg (1958-1962), including one year training in radiobiology for the identification of sites of action of radiolabeled drugs in the brain.
In 1963 moved to the United States on a one-year research fellowship of the Deutsche Forschungsgemeinschaft in the Department of Pharmacology (with L.J. Roth) at the University of Chicago to develop techniques for the microscopic tissue localization of drugs and other diffusible compounds. Extended research through completion of a Ph.D. in Pharmacology (1967) and continued at the University of Chicago as an Assistant Professor in Pharmacology (1967-1970). From 1970-1995, resident at the University of North Carolina at Chapel Hill as a Professor of Cell Biology and Pharmacology, with simultaneous appointments as a member of the Department of Anatomy (later Department of Cell Biology and Anatomy) and a member of the Department of Pharmacology, conducting research and teaching at the UNC-Chapel Hill Medical School, as well as a member of the Laboratories for Reproductive Biology (with H.S. Bennett). Professor Emeritus since 1995.
In addition was awarded an honorary degree from the University of Ulm for outstanding research in mechanisms of action of steroid hormones. Also received Humboldt Foundation Award for one-year position (1989-1990) as a visiting scientist at the University of Ulm (with C. Pilgrim). From 1992-1995 stationed in Japan as a resident consultant at Chugai Pharmaceutical Co., with continuing advisory role, for research on drug development, including sites of action of Vitamin D analogs (with Y. Nishii and N. Kubodera). From 1999 onwards, engaged as a visiting scientist at the Department of Histology, University of São Paulo , Brazil , with repeated stays for research on the localization and action of steroid hormones during early pregnancy (with T. Zorn). Organization of a three-day LEICA-workshop on “Drug Localization in Tissues and Cells” at the University of Heidelberg, 2003.
Development of Techniques
As clinical neurologist and psychiatrist, being confronted
with severe side effects of newly introduced psychotropic drugs, I
recognized the need to better understand sites and related mechanisms
of action. I abandoned work at the bedside in order to focus on
research of CNS receptors. No method existed for in vivo tissue and
cellular localization of non-covalently bound drugs. Development of a
suitable histochemical technique was considered very difficult, even
impossible, because of problems related to loss of tissue structure and
constituents, and translocation artifacts.
In association with Lloyd Roth at the University of Chicago, during a three-year period, I developed dry-mount and thaw-mount autoradiography by excluding any fluid phase during tissue treatment, preserving tissue structure for cellular resolution, and retaining tissue constituents at original in vivo sites. Several technical innovations provided the foundation for breakthrough, such as, simultaneous freeze-mounting on tissue holders, avoiding disruptive ice crystal formation and translocation, cutting thin frozen sections at temperatures previously considered impossible, eliminating the need for liquid fixation and embedding previously considered necessary by histologists, and replacing common multi-step dehydration and staining procedures by brief single-step staining, altogether minimizing treatment to follow the objective of studying the ‘unmolested tissue'.
Identification and Characterization of Drug Targets - New
Concepts
With receptor microscopic autoradiography – as the method is
now named – many discoveries were made in studies of steroid hormones,
drugs, and metabolic indicators. New targets were identified,
characterized by their topographic location and through combined
autoradiography-immunocytochemistry with radiolabeled compounds
and antibodies to cellular products. Detailed target maps of brain,
spinal cord and other organs provided unexpected data that gave rise to
new concepts, e.g.:
- Estrogen targets throughout the body in specific locations (e.g., heart atrium, testis Leydig cells, ovarian granulosa and theca cells, hair dermal papillae). Experts responded initially: ‘it has no meaning, it's everywhere; it is only localization.'
- Identification of estrogen-neuron circuits throughout the brain and spinal cord.
- Quantitative assessment of differential receptor binding in pituitary and other target cell populations.
- First demonstration of androgen and progestagen receptor neurons in regions of the brain.
- Concepts of steroid hormone target ABC-Circuits (Allocortex-Brain-Core) and MAHS (Multiple Activation of Heterogeneous Systems) for endocrine-autonomic regulation of aminergic-peptidergic neurons, extending the ‘Limbic System' concept.
- Discovery of multifunctional vitamin D targets in brain, pituitary, in over 50 tissues, not only in the classical ‘target organs' intestine, kidney, bone and parathyroid.
- Identification and mapping of brain-spinal cord vitamin D neuronal circuits (in contrast to a blood-brain barrier as identified with conventional radio-assays).
- New concept of the biological role of vitamin D: Regulation of calcium-homeostasis is only part of multifunctional seasonal adaptation and regulation of growth, cell proliferation and differentiation, reproduction, endocrine and exocrine secretions, immune and stress responses, cardio-vascular and gastro-intestinal functions..
- Thyroid hormone localization in brain regions and pituitary.
- Identification of retinoic acid target cell populations in brain and other tissues.
- Colocalization of progestin receptor and hormone, demonstrating hormone-independent nuclear presence of receptor (with J.-M. Gasc).
- Localization of steroid hormone binding sites in early chick embryos (with J.-M. Gasc).
- First demonstration and mapping of ecdysteroid binding sites in insect tissues and brain (witn H.-J. Bidmon).
- Identification of 2-deoxyglucose high activity neurons in medulla oblongata (with G. Duncan).
High Resolution in vivo Drug Localization for
- Measurement of Target Bioavailability and Target Pharmacokinetics,
- Prediction of Action, Side Effects, and Toxicity,
- Validation of In Vitro and High-Throughput Procedures, Non-invasive Imaging,
- Construction of a Drug Homunculus.
- Receptor Microsocopic Autoradiography has been perfected and applied during several decades as a high sensitivity-high resolution method for the identification and characterization of in vivo target sites of hormones and drugs, at the cellular-subcellular level within tissue and organ contexts – all of functional significance. Information on high specificity-low capacity sites of receptor binding advance recognition and prediction of clinical effects. False negatives/positives – common with less sensitive procedures - are minimized and erroneous investments on time and cost reduced. Results from receptor microautoradiography can serve as a guide for biochemical and functional follow-up, provide correlative data, complement radio-assays (others), and serve for validating results from ‘expedient' in vitro tests, and non-invasive imaging.
- Construction of a Drug-Target Homunculus from qualitative-quantitative microautoradiographic data enables functional fingerprinting of a specific drug, facilitates comparisons among drugs and analogs, and provides convenient surveys for regulatory agencies, clinicians, and patients.
- Regulatory agencies, pharmaceutical companies are challenged to consider results of this high-resolution histochemical method for the advancement of drug development and improved understanding of sites and mechanisms of drug action.
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Roth LJ and Stumpf WE, eds. AUTORADIOGRAPHY OF DIFFUSIBLE SUBSTANCES. 371 pp, Academic Press, New York, 1969.
Stumpf WE and Grant LD, eds. ANATOMICAL NEUROENDOCRINOLOG,
472 pp, S. Karger, Basel, 1975.
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Stumpf WE and Solomon H, eds. AUTORADIOGRAPHY AND CORRELATIVE IMAGING. Academic Press, San Diego, 1995.
Stumpf WE. DRUG
LOCALIZATION IN TISSUES AND CELLS. IDDC Press, Chapel Hill, NC,
2003.
The book on Drug Localization is available through the
University of North Carolina
Bookstore in Chapel Hill (UNC Student Stores, Chapel Hill , NC 27599 ).
Please direct order inquiries to:
Erica Eisdorfer
Phone: (919) 962-2420
Fax: (919) 962-9661
E-mail: eisdorfer@unc.edu
285 (Medline recorded), 550 + (total)
Selected Articles:
Stumpf WE. The dose makes the medicine. Drug Discovery Today. 2006 June; 11(11-12):550-5.
Stumpf WE. Drug
localization and targeting with receptor microscopic autoradiography.
J Pharmacol Toxicol Methods. 2005 Jan-Feb;51(1):25-40.
Hayakawa N, Kubota N, Imai N, Stumpf WE. Receptor microscopic autoradiography for the study of percutaneous absorption, in vivo skin penetration, and cellular-intercellular deposition. J Pharmacol Toxicol Methods. 2004 Sep-Oct;50(2):131-7.
Stumpf WE. Corpora
non agunt nisi in loco. Interactions between things do not "take place"
unless at "proper locus".
Drug Metab Dispos. 1996 May;24(5):507-8.
Stumpf WE. Vitamin
D sites and mechanisms of action: a histochemical perspective.
Reflections on the utility of autoradiography and cytopharmacology for
drug targeting. Histochem Cell Biol. 1995 Dec;104(6):417-27.
Birmingham MK, Sar M, Stumpf WE. Dexamethasone
target sites in the central nervous system and their potential
relevance to mental illness.
Cell Mol Neurobiol. 1993 Aug;13(4):373-86.
Stumpf WE, Bidmon HJ, Murakami R. Retinoic acid binding sites in adult brain, pituitary, and retina. Naturwissenschaften. 1991 Dec;78(12):561-2.
Duncan GE, Little KY, Koplas PA, Kirkman JA, Breese GR, Stumpf WE. Beta-adrenergic receptor distribution in human and rat hippocampal formation: marked species differences. Brain Res. 1991 Oct 4;561(1):84-92.
Bidmon HJ, Gutkowska J, Murakami R, Stumpf WE. Vitamin D receptors in heart: effects on atrial natriuretic factor. Experientia. 1991 Sep 15;47(9):958-62.
Duncan GE, Kaldas RG, Mitra KE, Breese GR, Stumpf WE. High activity neurons in the reticular formation of the medulla oblongata: a high-resolution autoradiographic 2-deoxyglucose study. Neuroscience. 1990;35(3):593-600.
Stumpf WE, Denny ME.
Vitamin
D (soltriol), light, and reproduction.
Am J Obstet Gynecol. 1989 Nov;161(5):1375-84.
Stumpf WE, Privette TH. Light, vitamin D and psychiatry. Role of 1,25 dihydroxyvitamin D3 (soltriol) in etiology and therapy of seasonal affective disorder and other mental processes. Psychopharmacology (Berl). 1989;97(3):285-94.
Stumpf WE, Sar M, Narbaitz R, Huang S, DeLuca HF. Autoradiographic localization of 1,25-dihydroxyvitamin D3 in rat placenta and yolk sac. Horm Res. 1983;18(4):215-20.
Heritage AS, Stumpf WE, Sar M, Grant LD. Brainstem catecholamine neurons are target sites for sex steroid hormones. Science. 1980 Mar 21;207(4437):1377-9.
Stumpf WE. "Peer"
review.
Science. 1980 Feb 22;207(4433):822-3.
Stumpf WE, Sar M, Reid FA, Tanaka Y, DeLuca HF. Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science. 1979 Dec 7;206(4423):1188-90.
Examples of autoradiograms prepared by Receptor Microscopic Autoradiography after injection of tritium-labeled vitamin D. The same preparation yields low-resolution surveys and high-resolution cellular-subcellular detail with quantitative differences of uptake and retention of radiolabeled compound. Among the over fifty target tissues identified and characterized by autoradiography a hierarchy of uptake and retention is recognizable. (For details see Stumpf: Drug Localization in Tissues and Cells, 2003; Drug localization and targeting with receptor microscopic autoradiography, 2005.)
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Brain amygdala central nucleus (upper picture) and spinal cord
lamina IX (lower picture) with labeled target neurons. Note the
differential nuclear concentration of radio-labeled compound. Most but
not all motor neurons are labeled.
Pituitary target cell population survey (upper picture). Colocalization with TSH-antibodies (brown cytoplasm in lower picture) characterizes many of the heavily labeled target cells as thyrotropes.
Duodenum with strong nuclear concentration of radiolabeled compound in absorptive epithelial cells – but not in Goblet cells (upper picture). In the low-magnification survey (lower picture) labeling exists in the nuclear regions of epithelium of intestinal villi and crypts but not in the muscularis. High level of radioactivity in the intestinal lumen - probably mostly liver-bile derived metabolites - with barrier between luminal content and villi.
Adrenal with radioactive labeling in medullary cells and blood vessels, recognizable at low magnification (upper picture). At high magnification (lower picture) nuclear concentration in medullary cells can be clearly identified. Also relatively high radioactivity in capillary sinusoids. In cortex zona reticularis (dark cells at left) no nuclear concentration of labeled compound exists under the conditions of the experiment.
Target identification derived from the application of receptor microautoradiography allows composition of a “drug homunculus” for drug-specific finger-printing, overviews, links for functional detail, facilitating functional and clinical follow-up, prediction of actions, side-effects, and toxicity.
The results thus obtained and insights gained suggest a change of concept. Although systemic calcium homeostasis is an important function of vitamin D, calcium binding proteins cannot be viewed as general guide to vitamin D sites and mechanisms of actions – as indicated in our comparative studies. Our data suggest:
The Main Biological Role of Vitamin D is Seasonal Adjustment of Vital Functions.
These include regulation of growth, reproduction, survival stress response; endocrine and exocrine secretion, cell proliferation, cognition and mood; neuro-motor, neuro-endocrine, and neuro-sensory functions, immune response, cardio-vascular and gastro-intestinal functions, regulation of calcium and other mineral levels, cell proliferation and protein synthesis-differentiation, others.
Comparative data with different steroid hormones and target-overlap further suggest interactive (cooperative and/or antagonistic) regulation of DNA by steroid messengers (Stumpf, 1995):
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Dermal Steroids |
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Gonadal Steroids |
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Adrenal Steroids |
From the microautoradiographic target recognition and related actions it follows that vitamin D has healing potential for prevention and treatment of various deficiencies and ailments, including old age: a PANACEA? If there is any compound that deserves being designated a panacea, the multifunctional heliogenic vitamin D appears a suitable candidate.
Philosophical consideration: “Vitamin D”, the term does not reflect its significance. I have used instead SOLTRIOL in several publications as a more appropriate designation. – Is there not a link to HERACLITUS' emanation of “ ever-living fire ”? The cosmic solar fire as the sustaining life force, providing wave length energies for Temperature , Visible Light , and Ultraviolet B (Soltriol).
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Contact: stumpfwe@email.unc.edu
Fec. April 2005