systems endocrinology

SYSTEMS BIOLOGY @ SYSTEMS MEDICINESYSTEMS ENDOCRINOLOGYJ. W. DIETRICH

SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 2

Conflict of Interest:

Patent application “System and method for deriving parameters for homeostatic feedback control of an individual” by S. L. Goede, J. W. Dietrichand Melvin K. S. Leow (A*STAR), WO/2014/088516, PCT/SG2013/000515


Gerhard Mercator (1512 – 1594)


Mercator Projection


Hammer-Aitov Projection


Goode homolosine Projection


Metabolic Maps

G. Michal (1965, 1999, 2012, 2014) Biochemical Pathways


Processing Structures

Mittelstaedt H. Triple-loop model of path control by head direction and place cells. Biological Cybernetics. 2000 Sep;83(3):261-70. PMID 11007300.


Correlation Networks

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Interaction Networks

www.bsse.ethz.ch


Metabolic Flux Analysis

wormbook.org


The Concept of Homeostasis

La fixité du milieu intérieur est la conditionde la vie libre, indépendante.

Claude Bernard (1813 – 1878)

The coordinated physiological processes which maintain most of the steady states in the organism are so complex and so peculiar to living beings … that I have suggested a special designation for these states, homeostasis. … It means a condition--a condition which may vary, but which is relatively constant.

Walter B. Cannon (1871 – 1945)


The Concept of Homeostasis

Regelungstechnik. Die technische Aufgabe und ihre wirtschaftliche, sozialpolitische und kulturpolitische Auswirkung.

Hermann Schmidt (1894 – 1968)

Cerebral Inhibition Meeting 1942Macy-Conferences 1946 – 1953

Cybernetics Group andNorbert Wiener


Homeostasis in Endocrinology

Moore, C.R. & Price, D. (1930) The question of sex hormone antagonism. Proceedings of the Society for Experimental Biology and Medicine , 28, 38–40.

Moore, C.R. & Price, D. (1932) Gonadal hormone functions, and the reciprocal influence between gonads and hypophysis with its bearing on the problem of sex hormone antagonism. American Journal of Anatomy, 50, 13–67.


Hohlweg, W. & Junkmann, K. (1932) Die hormonal-nervöse Regulierung des Hypophysenvorderlappens. Klinische Wochenschrift, 11, 321–323

Homeostasis in Endocrinology


Discovery of Thyroid Homeostasis

Roy Graham Hoskins(1880–1964)

Edwin Bennett Astwood(1909–1976)

E. B. Astwood (1936) Treatment of Hyperthyroidism with Thiourea and Thiouracil.JAMA 122;2: 78–81


Discovery of Thyroid Homeostasis

Roy Graham Hoskins(1880–1964)

Edwin Bennett Astwood(1909–1976)

R. G. Hoskins (1949) The Thyroid-Pituitary Apparatus as a Servo (Feed-Back) Mechanism. JCEM 9: 1429–31


Publications with PubMed search term "pituitary AND thyroid AND (feedback OR homeostasis)"


Early models


Modelling Techniques

Building Bricks for “Parametrically Isomorphic” Models

Elimination and Distribution

Michaelis-Menten Kinetics

Non-competitive Inhibition

Plasma Protein Binding


MiMe-NoCoDI Platform

For k parallel loops:

Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems 2006. 269-74. DOI: 10.13140/2.1.2400.2568

Equifinal solution:

Interative equation:


MiMe-NoCoDI Platform

Dietrich JW, Boehm, BO (2006) Equilibrium behaviour of feedback-coupled physiological saturation kinetics. Cybernetics and Systems 2006. 269-74. DOI: 10.13140/2.1.2400.2568


MiMe-NoCoDI Thyroid Model

Midgley, Hoermann,, Larisch and Dietrich (2013) Physiological states and functional

relation between thyrotropin and free thyroxine in thyroid health and disease: in

vivo and in silico data suggest a hierarchical model Journal of Clinical Pathology 66;4:

335–42





335–42

MiMe-NoCoDI Thyroid Model


MiMe-NoCoDI Model

Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res. 2012;2012:351864. doi: 10.1155/2012/351864. PMID 23365787


MiMe-NoCoDI Model



Pulsatile TSH Secretion

Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC. Pulsatile secretion ofthyrotropin in man. J Clin Endocrinol Metab. 1986 Sep;63(3):661-8. PMID3734036.


Pulsatile TSH Secretion

J. W. Dietrich, A. Tesche, C. R. Pickardt, and U. Mitzdorf,“Thyrotropic feedback control: evidence for an additionalultrashort feedback loop from fractal analysis,” Cyberneticsand Systems, vol. 35, no. 4, pp. 315–331, 2004.


T3 Dissociation

Hoermann, Midgley, Larisch and Dietrich,Is Pituitary TSH and adequate measure of

thyroid hormone-controlled homeostasisduring thyroxine treatment? EJE 2013: 168

271–80


NTIS / TACITUS

Dietrich, J. W., G. Landgrafe, E. H. Fotiadou (2012). TSH and thyrotropic agonists: Key actors in thyroid homeostasis. Journal of Thyroid Research, vol. 2012,

Article ID 351864, 29 pages, 2012. doi:10.1155/2012/351864





335–42

A Non-linear Model


Thyroid‘s Secretory Capacity

Symbol Explanation Value

T Dilution factor for T4 (reciprocal of apparent volume of distribution) 0.1 l-1

T Clearance exponent for T4 1.1 * 10-6 sec-1 DT EC50 for TSH 2.75 mU/l K41 Dissociation constant T4-TBG 2 * 1010 l/mol

K42 Dissociation constant T4-TBPA 2 * 108 l/mol

Dietrich JW, Stachon A, Antic B, Klein HH, Hering S. The AQUA-FONTIS study:protocol of a multidisciplinary, cross-sectional and prospective longitudinalstudy for developing standardized diagnostics and classification of non-thyroidalillness syndrome. BMC Endocr Disord. 2008 Oct 13;8:13. doi:10.1186/1472-6823-8-13. PMID 18851740

GT =βΤ (∆Τ + [ΤΣΗ ])(1+ Κ41[ΤΒΓ ] + Κ42[ΤΒΠΑ])[ΦΤ4 ]

αΤ [ΤΣΗ ]


AQUA FONTIS G Trial

94 Patients

Inclusion criteria:

ICU treatment ≥ 24 hours

TSH < 0,5 mIU/l

Exclusion criteria:

Pregnancy

Manifest AIDS disease

Impossibility to distinguish between hyperthyroidism and NTIS in a

retrospective manner

Jeyabalan et al. unpublished


Patients‘ Characteristics

Sex 26 female, 68 male

Age 16 – 92 years, median 67 years

APACHE II 2 – 31, median 12

SAPS II 7 – 71, median 40

Prognosis 12 died 82 survived

CPR 15 resuscitated 79 no CPR

LOSIH 1 – 159, median 13

LOSICU 1 – 89, median 5

Hyperthyroidism 12 with hyperthyroidism 82 with NTIS



Results

* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 1e-4 Jeyabalan et al. unpublished


Results



Diagnostic Utility

‡: Optimal Parameter Jeyabalan et al. unpublished


Algorithm


GT 25,56GD 8,5TSHI 1,27sTSHI –2,11

1,41–8,67 pmol/s20–40 nmol/s

1,3–4,1–2–+2


The “TSH Reference Range War”


The “TSH Reference Range War”

Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations inserum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002 Mar;87(3):1068-72. PMID 11889165.


MiMe-Log Model

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MiMe-Log Model

Goede SL, Leow MK, Smit JW, Dietrich JW. A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. Math Biosci. 2014 Mar;249:1-7. doi: 10.1016/j.mbs.2014.01.001. PMID 24480737


MiMe-Log Model

#Pre-Surgery TSH (mIU/L)

Pre-Surgery FT4 (pmol/L)

Setpoint TSH Setpoint FT4 |Delta TSH| |Delta FT4|

1 0.23 14.2 1.22 14.7 0.99 0.4

2 1.15 10.3 0.91 11.2 0.24 0.7

3 0.04 10.3 1.09 6.3 1.05 3.1

4 1.42 10.3 4.94 9.3 3.52 0.8

5 1.16 10.3 1.64 12.6 0.48 1.8

6 1.29 11.6 1.63 10.9 0.34 0.5

Mean 1.10 1.22

Cases from NOMOTHETICOS trial (clinicaltrials.gov NCT01145040)


Reconstruction of Set Point


SYSTEMS ENDOCRINOLOGYSYSTEMS BIOLOGY @ SYSTEMS MEDICINE

J. W. DIETRICH20141126

Doctoral Students:Antje AckermannAbira JeyabalanYarlini KanthasamyThabothini TharmalingamAline UrbanSeverina VasilevaGabi LandgrafeJan Giebelstein

Technical Assistance:Christine Fischer-Lahdo

Cooperation Partners:Elisabeth Conrad-OpelSteffen HeringRoland KöditzJohn E. M. MidgleyRudolf HörmannR. LarischRudolf KöhrleIna LehmphulJan W. SmitSam GoedeMelvin K. Leow

Advisors and General Support:C. Renate PickardtUlla Mitzdorf †Bernhard O. BöhmHarald KleinMatthew Marler

systems endocrinology

Science

isomorphic modelselimination

thyroidpituitary apparatus

homeostatic feedback

gonadal hormone functions

steady states

biological cybernetics

pubmed search term pituitary

hermann schmidt