Talk by Johannes W. Dietrich at the Systems Biology @ Systems Medicine Workshop, Lee Kong Chian School of Medicine (LKCMedicine), Novena Campus, Nanyang Institute of Technology in Health & Medicine (NITHM), Nanyang Technological University (NTU), Novena, Singapore, November 2014. From the abstract: Most, if not all vertebrate hormones are controlled by well-defined processing structures like feedback loops, antagonistic redundancy and reafference motifs. It is therefore not surprising that the development of systems theory and cybernetics between 1930 and 1950 ignited the transition to modern endocrinology. Today, education in endocrinology is based on systems models of homeostasis. Unfortunately, however, the potential of systems thinking is still only marginally utilized for clinical decision-making. Therefore, reasoning in endocrinology is usually restricted to pure statistics-based approaches that obstruct the pathway to personalised and participatory medicine. Reasons for this surprising unsuccessfulness of systems thinking in endocrinology include four impediments: (a) low quality of the majority of published mathematical models, (b) intellectual challenges that accompany both constructing and comprehending improved physiologically-based models, (c) insufficient education of physicians in cybernetics and systems science and (d) a lack of practically useful applications of these models. Luckily, we are today in the situation to have solutions for all four impediments. Key elements include the advent of new homeostatic models based on physiological and biochemical principles, a plethora of methods from systems biology – e.g. powerful simulation platforms – and, recently, the development of techniques based on mathematical modelling that allow for advanced diagnosis and treatment of endocrine diseases on an individualised basis. First clinical trials demonstrated the superiority of these novel methods over the previous purely statistic-based approaches. The transition to systems endocrinology, which both recollects old foundations and embraces new techniques, promises to pave the way to predictive, preventive, personalised and participatory (P4) medicine for patients suffering from highly prevalent disease like PCO syndrome, type 2 diabetes or thyroid disorders. This talk will provide an overview of the current state of systems thinking in endocrinology and of techniques that help to develop high-quality models that are ready to be applied for education and patient care.

1. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE
SYSTEMS ENDOCRINOLOGY
J. W. DIETRICH

2. 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. Dietrich
and Melvin K. S. Leow (A*STAR), WO/2014/088516, PCT/SG2013/000515

3. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 3
Gerhard Mercator (1512 – 1594)

4. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 4
Gerhard Mercator (1512 – 1594)

5. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 5

6. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 6
Mercator Projection

7. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 7
Hammer-Aitov Projection

8. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 8
Goode homolosine Projection

9. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 9

10. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 10
Metabolic Maps
G. Michal (1965, 1999, 2012, 2014) Biochemical Pathways

11. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 11
Metabolic Maps
G. Michal (1965, 1999, 2012, 2014) Biochemical Pathways

12. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 12
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.

13. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 13
Correlation Networks
GiebelsteinJetal..Theproteomicsignatureofinsulin-resistant
humanskeletalmusclerevealsincreasedglycolyticanddecreased
mitochondrialenzymes.Diabetologia.2012Apr;55(4):1114-27.
doi:10.1007/s00125-012-2456-x.PMID22282162.

14. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 14
Interaction Networks
www.bsse.ethz.ch

15. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 15
Metabolic Flux Analysis
wormbook.org

16. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 16
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)

17. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 17
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

18. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 18
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.

19. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 19
Hohlweg, W. & Junkmann, K. (1932) Die hormonal-nervöse Regulierung des
Hypophysenvorderlappens. Klinische Wochenschrift, 11, 321–323
Homeostasis in Endocrinology

20. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 20
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

21. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 21
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

22. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 22
Publications with PubMed search term
"pituitary AND thyroid AND (feedback OR homeostasis)"

23. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 23
Early models

24. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 24
Early models

25. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 25
Early models

26. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 26
Early models

27. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 27
Early models

28. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 28
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding

29. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 29
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding

30. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 30
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding

31. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 31
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding

32. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 32
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding

33. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 33
Modelling Techniques
Building Bricks for “Parametrically Isomorphic” Models
Elimination and Distribution
Michaelis-Menten Kinetics
Non-competitive Inhibition
Plasma Protein Binding

34. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 34
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:

35. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 35
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

36. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 36
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

37. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 37
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
MiMe-NoCoDI Thyroid Model

38. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 38
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

39. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 39
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

40. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 40
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

41. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 41
Pulsatile TSH Secretion
Greenspan SL, Klibanski A, Schoenfeld D, Ridgway EC. Pulsatile secretion of
thyrotropin in man. J Clin Endocrinol Metab. 1986 Sep;63(3):661-8. PMID
3734036.

42. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 42
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. 315–331, 2004.

43. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 43
T3 Dissociation
Hoermann, Midgley, Larisch and Dietrich,
Is Pituitary TSH and adequate measure of
thyroid hormone-controlled homeostasis
during thyroxine treatment? EJE 2013: 168
271–80

44. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 44
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

45. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 45

46. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 46
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
A Non-linear Model

47. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 47
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 * 10
10
l/mol
K42 Dissociation constant T4-TBPA 2 * 10
8
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
ˆGT =
βΤ (∆Τ + [ΤΣΗ])(1+ Κ41[ΤΒΓ ]+ Κ42[ΤΒΠΑ])[ΦΤ4 ]
αΤ [ΤΣΗ]

48. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 48
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

49. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 49
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
Jeyabalan et al. unpublished

50. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 50
Results
* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 1e-4 Jeyabalan et al. unpublished

51. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 51
Results
Jeyabalan et al. unpublished

52. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 52
Results

53. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 53
Diagnostic Utility
‡: Optimal Parameter Jeyabalan et al. unpublished

54. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 54
Algorithm

55. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 55
GT 25,56
GD 8,5
TSHI 1,27
sTSHI –2,11
1,41–8,67 pmol/s
20–40 nmol/s
1,3–4,1
–2–+2

56. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 56
GT 25,56
GD 8,5
TSHI 1,27
sTSHI –2,11
1,41–8,67 pmol/s
20–40 nmol/s
1,3–4,1
–2–+2

57. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 57
GT 25,56
GD 8,5
TSHI 1,27
sTSHI –2,11
1,41–8,67 pmol/s
20–40 nmol/s
1,3–4,1
–2–+2

58. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 58
The “TSH Reference Range War”

59. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 59
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 Mar;87(3):1068-72. PMID 11889165.

60. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 60

61. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 61
MiMe-Log Model
GoedeSL,LeowMK,SmitJW,KleinHH,DietrichJW.
Hypothalamus-pituitary-thyroidfeedbackcontrol:implicationsof
mathematicalmodelingandconsequencesforthyrotropin(TSH)
andfreethyroxine(FT4)referenceranges.BullMathBiol.2014
Jun;76(6):1270-87.doi:10.1007/s11538-014-9955-5.
PMID24789568.

62. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 62
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

63. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 63
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)

64. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 64
Reconstruction of Set Point

65. SYSTEMS BIOLOGY @ SYSTEMS MEDICINE SYSTEMS ENDOCRINOLOGY | 21.02.15 65
SYSTEMS ENDOCRINOLOGY
SYSTEMS BIOLOGY @ SYSTEMS MEDICINE
J. W. DIETRICH
20141126
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