Systems Endocrinology: Successful Examples of Translational Medicine

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SYSTEMS BIOLOGY _at_ SYSTEMS MEDICINE SYSTEMS
ENDOCRINOLOGY J. W. DIETRICH
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Conflict of Interest Patent application System
and method for deriving parameters for
homeostatic feedback control of an individual
by S. L. Goede, J. W. Dietrich and Melvin K. S.
Leow (ASTAR), WO/2014/088516, PCT/SG2013/000515
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Gerhard Mercator (1512 1594)
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Gerhard Mercator (1512 1594)
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Mercator Projection
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Hammer-Aitov Projection
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Goode homolosine Projection
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Metabolic Maps
G. Michal (1965, 1999, 2012, 2014) Biochemical
Pathways
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Metabolic Maps
G. Michal (1965, 1999, 2012, 2014) Biochemical
Pathways
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Processing Structures
Mittelstaedt H. Triple-loop model of path control
by head direction and place cells. Biological
Cybernetics. 2000 Sep83(3)261-70. PMID 11007300.
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Correlation Networks
Giebelstein J et al.. The proteomic signature of
insulin-resistant human skeletal muscle reveals
increased glycolytic and decreased mitochondrial
enzymes. Diabetologia. 2012 Apr55(4)1114-27.
doi 10.1007/s00125-012-2456-x. PMID 22282162.
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Interaction Networks
www.bsse.ethz.ch
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Metabolic Flux Analysis
wormbook.org
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The Concept of Homeostasis
La fixité du milieu intérieur est la condition de
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)
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The Concept of Homeostasis
Regelungstechnik. Die technische Aufgabe und ihre
wirtschaftliche, sozialpolitische und
kulturpolitische Auswirkung.
Hermann Schmidt (1894 1968)
Cerebral Inhibition Meeting 1942 Macy-Conferences
1946 1953
Cybernetics Group and Norbert Wiener
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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, 3840. 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, 1367.
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Homeostasis in Endocrinology
Hohlweg, W. Junkmann, K. (1932) Die
hormonal-nervöse Regulierung des
Hypophysenvorderlappens. Klinische Wochenschrift,
11, 321323
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Discovery of Thyroid Homeostasis
Roy Graham Hoskins (18801964)
Edwin Bennett Astwood (19091976)
E. B. Astwood (1936) Treatment of Hyperthyroidism
with Thiourea and Thiouracil. JAMA 1222 7881
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Discovery of Thyroid Homeostasis
Roy Graham Hoskins (18801964)
Edwin Bennett Astwood (19091976)
R. G. Hoskins (1949) The Thyroid-Pituitary
Apparatus as a Servo (Feed-Back) Mechanism. JCEM
9 142931
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Publications with PubMed search term "pituitary
AND thyroid AND (feedback OR homeostasis)"
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Early models
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Early models
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Early models
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Early models
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Early models
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Modelling Techniques
Building Bricks for Parametrically Isomorphic
Models
Elimination and Distribution
Non-competitive Inhibition
Michaelis-Menten Kinetics
Plasma Protein Binding
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Modelling Techniques
Building Bricks for Parametrically Isomorphic
Models
Elimination and Distribution
Non-competitive Inhibition
Michaelis-Menten Kinetics
Plasma Protein Binding
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Modelling Techniques
Building Bricks for Parametrically Isomorphic
Models
Elimination and Distribution
Non-competitive Inhibition
Michaelis-Menten Kinetics
Plasma Protein Binding
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Modelling Techniques
Building Bricks for Parametrically Isomorphic
Models
Elimination and Distribution
Non-competitive Inhibition
Michaelis-Menten Kinetics
Plasma Protein Binding
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Modelling Techniques
Building Bricks for Parametrically Isomorphic
Models
Elimination and Distribution
Non-competitive Inhibition
Michaelis-Menten Kinetics
Plasma Protein Binding
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Modelling Techniques
Building Bricks for Parametrically Isomorphic
Models
Elimination and Distribution
Non-competitive Inhibition
Michaelis-Menten Kinetics
Plasma Protein Binding
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MiMe-NoCoDI Platform
For k parallel loops
Interative equation
Equifinal solution
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
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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
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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 664 33542
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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 664 33542
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MiMe-NoCoDI Model
Dietrich JW, Landgrafe G, Fotiadou EH. TSH and
Thyrotropic Agonists Key Actors in Thyroid
Homeostasis. J Thyroid Res. 20122012351864.
doi 10.1155/2012/351864. PMID 23365787
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MiMe-NoCoDI Model
Dietrich JW, Landgrafe G, Fotiadou EH. TSH and
Thyrotropic Agonists Key Actors in Thyroid
Homeostasis. J Thyroid Res. 20122012351864.
doi 10.1155/2012/351864. PMID 23365787
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MiMe-NoCoDI Model
Dietrich JW, Landgrafe G, Fotiadou EH. TSH and
Thyrotropic Agonists Key Actors in Thyroid
Homeostasis. J Thyroid Res. 20122012351864.
doi 10.1155/2012/351864. PMID 23365787
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Pulsatile TSH Secretion
Greenspan SL, Klibanski A, Schoenfeld D, Ridgway
EC. Pulsatile secretion of thyrotropin in man. J
Clin Endocrinol Metab. 1986 Sep63(3)661-8.
PMID 3734036.
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Pulsatile TSH Secretion
J. W. Dietrich, A. Tesche, C. R. Pickardt, and U.
Mitzdorf, Thyrotropic feedback control evidence
for an additional ultrashort feedback loop from
fractal analysis, Cybernetics and Systems, vol.
35, no. 4, pp. 315331, 2004.
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T3 Dissociation
Hoermann, Midgley, Larisch and Dietrich, Is
Pituitary TSH and adequate measure of thyroid
hormone-controlled homeostasis during thyroxine
treatment? EJE 2013 168 27180
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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. doi10.1155/2012/351864
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A Non-linear 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 664 33542
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Thyroids Secretory Capacity
Dietrich JW, Stachon A, Antic B, Klein HH, Hering
S. The AQUA-FONTIS studyprotocol of a
multidisciplinary, cross-sectional and
prospective longitudinalstudy for developing
standardized diagnostics and classification of
non-thyroidalillness syndrome. BMC Endocr Disord.
2008 Oct 13813. doi10.1186/1472-6823-8-13.
PMID 18851740
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AQUA FONTIS G Trial

• 94 Patients
• Inclusion criteria
• ICU treatment 24 hours
• TSH lt 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
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Patients Characteristics
Sex 26 female, 68 male 26 female, 68 male
Age 16  92 years, median 67 years 16  92 years, median 67 years
APACHE II 2 31, median 12 2 31, median 12
SAPS II 7 71, median 40 7 71, median 40
Prognosis 12 died 82 survived
CPR 15 resuscitated 79 no CPR
LOSIH 1 159, median 13 1 159, median 13
LOSICU 1  89, median 5 1  89, median 5
Hyperthyroidism 12 with hyperthyroidism 82 with NTIS
Jeyabalan et al. unpublished
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Results
p lt 0.05, p lt 0.01, p lt 0.001, p lt
1e-4
Jeyabalan et al. unpublished
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Results
Jeyabalan et al. unpublished
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Results
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Diagnostic Utility
Jeyabalan et al. unpublished
Optimal Parameter
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Algorithm
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GT 25,56 GD 8,5 TSHI 1,27 sTSHI 2,11
1,418,67 pmol/s 2040 nmol/s 1,34,1 22
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GT 25,56 GD 8,5 TSHI 1,27 sTSHI 2,11
1,418,67 pmol/s 2040 nmol/s 1,34,1 22
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GT 25,56 GD 8,5 TSHI 1,27 sTSHI 2,11
1,418,67 pmol/s 2040 nmol/s 1,34,1 22
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The TSH Reference Range War
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The TSH Reference Range War
Andersen S, Pedersen KM, Bruun NH, Laurberg P.
Narrow individual variations in serum T(4) and
T(3) in normal subjects a clue to the
understanding of subclinical thyroid disease. J
Clin Endocrinol Metab. 2002 Mar87(3)1068-72.
PMID 11889165.
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MiMe-Log Model
Goede SL, Leow MK, Smit JW, Klein HH, Dietrich
JW. Hypothalamus-pituitary-thyroid feedback
control implications of mathematical modeling
and consequences for thyrotropin (TSH) and free
thyroxine (FT4) reference ranges. Bull Math Biol.
2014 Jun76(6)1270-87. doi 10.1007/s11538-014-9
955-5. PMID 24789568.
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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 Mar2491-7. doi 10.1016/j.mbs.2014.
01.001. PMID 24480737
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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 Mean Mean Mean Mean 1.10 1.22
Cases from NOMOTHETICOS trial (clinicaltrials.gov
NCT01145040)
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Reconstruction of Set Point
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Doctoral Students Antje Ackermann Abira
Jeyabalan Yarlini Kanthasamy Thabothini
Tharmalingam Aline Urban Severina Vasileva Gabi
Landgrafe Jan Giebelstein Technical
Assistance Christine Fischer-Lahdo Cooperation
Partners Elisabeth Conrad-Opel Steffen
Hering Roland Köditz John E. M. Midgley Rudolf
Hörmann R. Larisch Rudolf Köhrle Ina Lehmphul Jan
W. Smit Sam Goede Melvin K. Leow Advisors and
General Support C. Renate Pickardt Ulla Mitzdorf
Bernhard O. Böhm Harald Klein Matthew Marler
SYSTEMS ENDOCRINOLOGY SYSTEMS BIOLOGY _at_ SYSTEMS
MEDICINE
J. W. DIETRICH 20141126