Curate Hepatology Models: An Update
Harvey Ho, Hanne Nielsen, Peter Hunter
Bioengineering Institute
University of Auckland, New Zealand
CellML Workshop, Auckland, New Zealand
13 March 2012
Outline
 Background
 Why systems biology?
 International Initiatives
 Hepatology Model Curation
 Previous work
 Models added
 Issues arising
 Future Direction - Some personal thoughts
 Create cutting-edge models
 Clinical connection
2
Section I: Background
3
Background
Why systems biology?
Image source:
SBMC’2012
“The rhythmicity of the heart is not encoded at a subcellular level – so looking for a genetic
basis for this behaviour, for example, is futile - but first emerges at the level of the individual cell.
It is modulated as the other layers of the system are combined: from an individual cell, the
electrophysiology of its encapsulating membrane, up to the tissue level and finally whole organ”
- Denis Nobel
Background
Systems biology for the liver:
•
•
The same methodology applies to the liver
‘Top-down’ and ‘Bottom-up’
*Abbott, Germans cook up live project, Nature, Vol 468, P879
Int’l Research
HepatoSys project
• €36M project, 2004-2009 by the German Federal
Ministry of Education and Research (BMBF)
• Investigates all processes within the liver, with a focus
on hepatocytes
6
Int’l Research
Virtual Liver Network
1. with funding €42M for 5 years
2. ~250 scientists in 69 research groups in Germany
3. Three major areas of focus:
– The Liver Cell
– Beyond the Cell
– Integration and Translation
*Abbott, Germans cook up live project, Nature, Vol 468, P879, 2010
7
Section II: Curate Hepatology Models
8
Previous work
• Papers sourced from HepatoSys publication (Jan 2009)
• Total papers: 249
• Keyword ‘Platform Modelling’: 58
• Selection criteria
– Equation formation
– Parameter completeness
– Initial conditions
9
Previous work
amino acid
metabolism
Acikgoz 2009
Guthke 2006
Drug biotransformation
liver regeneration
Chauhan 2008
Klamt 2003
Issues Arising
• Uncodable Models
• Missing Units and Initial Values
- have to make guesses -> uncertainty
• Errors in Printed Papers
• Invalid emails for published author contacts
11
Curate New Models
Methods/Strategy
• Smaller models first, then larger models
• Older models first, then newer models
• Connection between models
• Model evolution
• Collaborators, strategically important
Examples
• Models of Prof. Ursula Kummer (Dept of Modeling of
Biological Processes, Uni of Heidelberg)
Larsen_2003
Grubelnik _2001
Kummer_2000
Marhl_2000
1. Grubelnik et al, ‘Mitochondria regulate the amplitude of simple and
complex calcium oscillations’, 2001 Biophysical Chemistry, 94, 59-74.
2. Kummer et al, ‘Switching from Simple to Complex Oscillations in Calcium
Signaling’, 2000 Biophysical Journal, 79, 1188-1195
Examples
•
Model evolution diagram
Gall_2009
Gall_2000
Cardenas_1996
Dupont_1992
Goldbeter, Berridge
1. Gall et al, ‘Activation of the Liver Glycogen Phosphorylase by Ca2+ Oscillations: a
Theoretical Study‘, 2000, Journal of Theoretical Biology, 207, 445-454
2. Cardenas and Goldbeter, ‘The Glucose-induced Switch Between Glycogen
Phosphorylase and Glycogen Synthase in the Liver: Outlines of a Theoretical
Approach’, 1996 Journal of Theoretical Biology, 182, 421-426.
Other curated models
Swat_2004
mammalian G1/S transition
metabolism
schmitmeier_2007
Other curated models
Section III: Future Direction
Some Personal Thoughts
17
CellML
• What we have learned?
– Model evolution
• Hierarchy
• Public, private interface
– Understand the underlying physiology
– Different components integrated to form a new model
– Work with key research groups
• User requirement
• Proactive curating
Clinical Connection
• Collaboration with transplantation surgeon,
interventional radiologists
• Liver resection to treat tumour
• Liver transplantation
Connect to microscale models
Image courtesy of Dr. Adam Bartlett
19
Clinical connection
Dedicated to Prof. Andrew Pullan (1963-2012)
“The other drug ipilmumab cannot be considered an option at this stage as my liver is
too compromised to be able to handle it.”, 14 Jul 2011 http://andrewsrecovery.blogspot.co.nz/
Circulation model
•
– Hepatotoxity
– mitochondrial damage
Homeostasis of hepatocytes,
inflammatory mediator secretion from
Kupffer cells
Gene signature for hepatotoxity
Drug induced liver injury
– reactive metabolite effects
– …
•
Toxicity pathways -> safer drugs
Thanks for your attention.
Questions?
21