SYSTEMS BIOLOGY AND SYSTEMS MEDICINE: TOWARDS A PRECISION MEDICINE September 26-30, 2016

1. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 1
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And now … Questions for YOU.
Again, the same three groups discuss, come to a conclusion
and present:
Marco
1. Given that several diseases depend on cell types and/or dynamically evolving sub‐
populations, what contribution could whole‐cell models give to precision
medicine?
2. Digital (whole‐cell/multi‐cell computational models) versus mouse avatars
(xenopatients) in personalized medicine: which is the one to focus on and why?
Matteo
1. Which are possible ways to integrate the various layers of cellular regulation (i.e.,
signaling, cell cycle, metabolism, gene regulation)?
2. When integrating regulatory layers, which constraints – if any – should one
implement in order for the integration process to be as close as possible to the real
cell behavior?
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Closing session

2. Como Systems Medicine course 30/09/2016
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CASYM form
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I would like to have hands-on tutorials
A. Yes
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It should be a good idea to focus the school on
one disease (e.g. the systems biology of cancer)
A. Yes
B. No
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It should be a good idea to focus the school on
one disease (e.g. the systems biology of cancer)
A.
B.
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No
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3. Como Systems Medicine course 30/09/2016
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Should this focus be effected, then I would prefer
the topic to be
A. Cancer
B. Metabolic Syndrome (=diabetes, obesity etc)
C. Heart disease
D. Inborn errors of metabolism
E. Infectious disease
F. Immune diseases inclusive of allergies
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the topic to be
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A.
B.
C.
D.
E.
F.
Cancer
Metabolic Syndrome
(=diabetes, obesity etc)
Heart disease
Inborn errors of
metabolism
Infectious disease
Immune diseases inclusive
of allergies
16.7%
33.3%
50.0%
66.7%
83.3%
100.0%
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A good registration fee for the school should be
A. <200 euro; 1 foreign speaker
B. 200< < 400 euro; 4 foreign speakers
C. 400 < < 600 euro: 10 foreign speakers
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A good registration fee for the school should be
A.
B.
C.
<200 euro; 1
foreign speaker
200< < 400
euro; 4 foreign
speakers
400 < < 600
euro: 10 foreign
speakers
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How many students/participants would you find
optimal for a Como school of advanced studies?
A. <30
B. 30 < < 60
C. 60<
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How many students/participants would you find
optimal for a Como school of advanced studies?
A.
B.
C.
<30
30 < < 60
60<
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4. Como Systems Medicine course 30/09/2016
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I think a luxurious envirnment like this villa is great
for the school (though expensive)
A. Yes
B. No
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for the school (though expensive)
A.
B.
Yes
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What did we learn?
In a nutshell
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Hans Westerhoff:
Towards Precision Biology and Medicine
• The Future in 2000
– What remained to be discovered
• Life at the edge and the origin of Life
– How to get your Carbon and Gibbs energy precisely (‐‐> Thierry Mondeel)
• Towards precision medicine
– Individualized medicine from PKU to Parkinson’s? (Alexey Kolodkin)
– Transcription dynamics, cell‐cell heterogeneity and cancer ( Stefania
Astrologo)
– How understanding might matter: the Janus head of acute and chronic
inflammation
• Serving the community
– Infrastructure systems Biology Europe (ISBE@NL): make me a model coalition
(Alexey Kolodkin)
– Replica models, virtual human
How can the metabolic map lead to new
understanding of disease?
A. Phenylketonuria leads to lack of brain development
because of lack of tyr import into brain and because tyr
is required for dopamine synthesis
B. Because phenylalanine increases and is metabolized to
the toxic phenylketone that is secreted into the urine
C. Because lack of the enzyme phenylalanine hydroxylase
causes a reduced flux down that pathway and a
reduced synthesis of fumarate The question will open when you
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5. Como Systems Medicine course 30/09/2016
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How can the metabolic map lead to new
understanding of disease?
Closed
A.
B.
C.
Phenylketonuria leads to lack of brain
development because of lack of tyr...
Because phenylalanine increases and is
metabolized to the toxic...
Because lack of the enzyme phenylalanine
hydroxylase causes a reduced flux...
33.3%
66.7%
100.0%
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Why is multifactorial disease complex in more than
two ways?
A. Because 26 000 genes are involved
B. It requires multiple factors to be altered, which can be
remote, and not always the same factors, and differing
between individuals
C. Because there are so many (thousands) of metabolites
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Why is multifactorial disease complex in more than
two ways?
Closed
A.
B.
C.
Because 26 000 genes are
involved
It requires multiple factors to
be altered, which can be
remote, and not always the
same factors, and differing
between individuals
Because there are so many
(thousands) of metabolites
33.3%
66.7%
100.0%
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Enzo Medico:
Towards Precision Biology and Medicine
• Tumor heterogeneity
• Individual progression of tumors
• miRNA involved in regulation
• It makes sense to hunt for exceptions: try to cure the outliers
• Stromal involvement
• Visualization of data for the physician
– Replica models, virtual human
mRNA signature of tumors is signature of
A. cancer stem cells
B. tissue stem cells
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6. Como Systems Medicine course 30/09/2016
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mRNA signature of tumors is signature of
A.
B.
cancer stem cells
tissue stem cells
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Giancarlo Mauri:
Towards Precision Biology and Medicine
Reconstruction of cancer progression:
As ensemble,
or
As individual cells
How to figure out temporal sequence from random samples without
time stamp?
– Replica models, virtual human
What was an important assumption of the
approach?
A. Gene expression can be measured
B. Features are acquired, never lost
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What was an important assumption of the
approach?
A.
B.
Gene expression can be
measured
Features are acquired,
never lost
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7. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 7
Thierry Mondeel :
Towards Precision Biology and Medicine
• How to map out fluxes on a genome wide map
• Precise specification of modelling methodology required for
reproducible science
• Various combinations of redox enzymes lead to various ATP/acetate
yields and biotechnology yields
– Replica models, virtual human
Unlike the experimental literature, the modelling
literature is robust
A. No
B. Yes
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Unlike the experimental literature, the modelling
literature is robust
A.
B.
No
Yes
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Sampsa Hautaniemi:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Factors can be both pro‐ and anti apoptotic (e.g. JNK)
– Resistance due to pre‐existing subpopulation
– Pre‐target, on‐target, post‐target and off‐target
resistance
– A model with on‐ and post‐target resistance that works
Drug resistance of tumors is mostly due to the
cells adapting to the drug. True or false?
A. True
B. False
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8. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 8
Drug resistance of tumors is mostly due to the
cells adapting to the drug. True or false?
A.
B.
True
False
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Damjana Rozman:
Towards Precision Biology and Medicine
– Replica models, virtual human
– CASYM
– NAFLD
– Strong effect of gender
– Existing genome‐wide metabolic map (Hepatonet) not
suitable for pathology
– NAFLD causing switch from:
• gluconeogenesis from lactate to
• gluconeogenesis from glycerol
– STEATONET model
– using connections of liver cells to other cells is crucial
Is the time of day one determines cholesterol
metabolism important?
A. Yes
B. No
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Is the time of day one determines cholesterol
metabolism important?
A.
B.
Yes
No
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9. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 9
Alexey Kolodkin:
Towards Precision Biology and Medicine
– Replica models, virtual human
– ISBE.NL: infrastructure; make‐me‐a‐model and
standards
– MAPkinase pathway model
– Parkinson’s disease model with four design principles
understood
– Coffee helping against PD may be understood
Why is a MAP kinase pathway not a MAP kinase
pathway?
A. It starts with Ras not MAP
B. It would cause cancer if it was
C. It is only determined by Ras attachment to the
membrane; pathway is irrelevant
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Why is a MAP kinase pathway not a MAP kinase
pathway?
Closed
A.
B.
C.
It starts with Ras not
MAP
It would cause cancer if it
was
It is only determined by
Ras attachment to the
membrane; pathway is
irrelevant
33.3%
66.7%
100.0%
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Walter Kolch:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Euler (Königsbergen) first to show importance of
abstractions (models)
– Adaptation important in determining drug response
– Negative feedback amplifier: takes away drug effect
– Unless drug affects the amplification itself
– Only 30% of patients respond to a drug
Which is the more promising approach for the future?
A. Organoids
B. Collecting all human information
C. Xenografts
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10. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 10
Which is the more promising approach for the
future?
A.
B.
C.
Organoids
Collecting all
human
information
Xenografts
33.3%
66.7%
100.0%
Closed
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Gennaro Piccialli:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Chemical drug design
– Lipitor best selling drug: 14 billion$
– Most drugs promiscuous (7 targets)
– Decorated nanoparticles
Which disease was the first blockbuster drug for?
A. Tuberculosis
B. Spanish flue
C. Syphillis
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Which disease was the first blockbuster drug for?
A.
B.
C.
Tuberculosis
Spanish flue
Syphillis
33.3%
66.7%
100.0%
Closed
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11. Como Systems Medicine course 30/09/2016
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Hans Lehrach:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Broken arm as example of personalized medicine
– Health care in Europe 1 Trillion €/year
– Genome sequence, deep sequencing mRNA, somatic
variants.
– After training linear kinetic model: predictive success
– Reverse engineering of parameters rather than Monte
Carlo approach
– Pharma and personalized medicine: greatly reduced
attrition rate will pay for it
Why are European physicians against the use of
virtual patient?
A. Cannot get sued by patient for giving wrong, first-line
treatment
B. Better medical ethical code
C. Because it is more expensive
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Why are European physicians against the use of
virtual patient?
Closed
A.
B.
C.
Cannot get sued by
patient for giving
wrong, first‐line
treatment
Better medical ethical
code
Because it is more
expensive
33.3%
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Lilia Alberghina:
Towards Precision Biology and Medicine
– Replica models, virtual human
– K‐Ras effect on cancer is really due to uncoupling of gln
and glucose metabolism
– Cancer metabolic rewiring: due to limited, but non zero
oxygen; partical gln oxidation to lactate, glucose to
lactate
– Branched anti‐TCA cycle
Should primary approach to cancer target
signalling, gene expression or metabolism?
A. signalling
B. transcription
C. metabolism
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12. Como Systems Medicine course 30/09/2016
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Should primary approach to cancer target
signalling, gene expression or metabolism?
A.
B.
C.
signalling
transcription
metabolism
33.3%
66.7%
100.0%
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Chiara Damiani:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Flux balance analysis
– ATP cost biomass due to fitting
– Results depend on assumed maintenance
– Sampling of solutions with random objective functions
– Natural segregation into +/‐ Warburg, +/‐ growth
phenotypes
Is growth rate the only objective to be considered?
A. Yes, cancer cells outgrow others
B. No, other solutions may arise because of drizzle of
mutations
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Is growth rate the only objective to be considered?
Closed
A.
B.
Yes, cancer cells
outgrow others
No, other solutions
may arise because
of drizzle of
mutations
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13. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 13
Matteo Barberis:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Cyclins direct cyclin dependent kinases
– Some with dual function
Marco Vanoni:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Computational model, versus
– Avatars in mouse
– Cell type important for disease
Is a model of the human cell good enough to
understand disease?
A. Yes
B. No
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Is a model of the human cell good enough to
understand disease?
A.
B.
Yes
No
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Marco Viceconti:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Bone and skeletal modelling possible
– Multi‐scale modelling from hip to cell
– Existing molecular data not good enough
– Virtual Physiological Human
– VPH to the society

14. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 14
Is systems biology enough to understand disease?
A. Yes, because drugs are molecules
B. No, because all is decided at tissue level
C. No, because it is also decided at tissue level
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Is systems biology enough to understand disease?
Closed
A.
B.
C.
Yes, because drugs are
molecules
No, because all is decided at
tissue level
No, because it is also decided
at tissue level
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Anneke Koster:
Towards Precision Biology and Medicine
– Replica models, virtual human
– Forensics is developing like systems medicine
– Much integration of heterogeneous data required
– Learning from thousands of other cases (retrospective
data in repository)
Each crime scene is different. Can they learn from
each other?
A. Yes, because criminals repeat themselves
B. No, it is a can of worms (all different)
C. Yes, because crimes can only be committed according
to a limited set of models
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Each crime scene is different. Can they learn from
each other?
Closed
A.
B.
C.
Yes, because criminals
repeat themselves
No, it is a can of worms (all
different)
Yes, because crimes can
only be committed
according to a limited set
of models
33.3%
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15. Como Systems Medicine course 30/09/2016
Westerhoff et al: closure Page 15
Thanks
• The Alessandro Volta Foundation and Prof Giulio
Casati for generous support and the beautiful
accommodation
• The centers (SysBio.IT) for support
• Prof Alberghina: organization planning
• Max: Organization
• Speakers, tutors: tremendous effort in making
things debatable
• You: active participation
See you in
Stockholm,
Como
Or other places