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SUMMARY:Is it the Genome that Throws Dice Then? Statistical Thermodynamics
  for Individualized Medicine
DTSTART:20180522T161500
DTSTAMP:20260509T115333Z
UID:b58166acd5eb58f3f27d17fcc1678f5c1f6a8fcc6e469b7494d04eeb
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. Hans V. Westerhoff\, University of Amsterdam and VU Univ
 ersity in Amsterdam (NL)\,  and University of Manchester (UK)\nBIOENGINEE
 RING SEMINAR\n\nAbstract:\nUnderstanding how biological functions emerge f
 rom all molecular interactions is the aim of systems biology. However\, th
 e complexity of 25\,000 (or even 300\,000) genes and their expression prod
 ucts is mind-boggling. Is this complexity prohibitive? Yes\, and No! I wil
 l first show how considerations of biological function\, as well as newly 
 recognized non-equilibrium thermodynamics principles\, plus a focus on pin
 pointing what really matters\, enables some modes of understanding. This m
 ay be useful\, for instance\, by enabling differential network-based drug 
 design.\n \nSome models achieve quite accurate predictions. Paradoxically
  these predictions are sometimes even too accurate. Predicted properties t
 urn out to be uncertain not just due to experimental limitations\, but als
 o because of heterogeneity in cell populations. We formulate this implicat
 ion of heterogeneity as an uncertainty principle\, which we compare with t
 hat of Heisenberg. Indeed\, even clonal cells in a tissue appear to be het
 erogeneous in their phenotype. We will show how an epigenetic transcriptio
 n-clock mechanism could lead to transcription bursting and to substantial 
 noise in mRNA and perhaps protein levels. We shall revive a rule that rela
 tes the variance to the mean of molecule number and that requires a limite
 d amount of molecular information: statistical thermodynamics enters. If d
 ynamics is slow enough\, the corresponding cell-cell heterogeneity may inc
 rease drug resistance of the cell population. This type of statistical mec
 hanical noise and uncertainty may explain why drug resistance is so hard t
 o prevent.\n \nEinstein long opposed the fundamental nature of Heisenberg
 ’s uncertainty principle\, contending that one should just acquire more 
 information about the elementary particles. Bohr rightly contended that it
  is impossible to acquire that information without completely perturbing t
 he system. Medicine appears to be home to an uncertainty principles that i
 s again similar to that of Heisenberg. I shall argue that this time Einste
 in would have been right: By putting in more of the patient’s molecular 
 information one should be able to remove much of the uncertainty in diagno
 sis and therapy outcome. I shall exemplify for inborn errors of metabolism
  and the metabolic map.\n \nWe shall show how an integration of precise e
 xperimentation\, molecular tinkering\, mathematical modelling and analysis
 \, may enable us to understand or even revert deregulated behaviour of bio
 logical systems.\n \nWe compare this uncertainty to that of Heisenberg’
 s predictions. Yet\, predictions In a linear metabolic pathway of 10 enzym
 es there is only a single flux at steady state. We will show how essential
 ly this complexity-reducing feature of metabolic networks\, with genome-wi
 de integration of genomic and biochemical data\, plus a pinch of mathemati
 cs enables the understanding of inborn errors of metabolism. Accommodating
  the different instantiations that individuals have of these networks\, we
  shall illustrate how human genome functioning is ‘noisy’. This noise/
 diversity in network behavior makes many human diseases elusive and multif
 actorial\, and individualized medicine crucial.\n \nBio:\nHans V. Westerh
 off is Professor of Systems Biology at the Universities of Manchester and 
 Amsterdam and of Molecular Cell Physiology at the VU University in Amsterd
 am.\nHe is one of the founding Fathers of Systems Biology and one of the i
 ntellectual leaders of the field.\nProf. Westerhoff obtained his Ph.D. in 
 1983 from the University of Amsterdam for investigations of non-equilibriu
 m thermodynamics and the control of biological thermodynamics under the su
 pervision of Professor Karel van Dam.\nProf. Westerhoff studies how biolog
 ical functions emerge in the complex interactions between the components o
 f living systems.\nHis work has resulted in more than 400 publications and
  seminal contributions to the Systems Biology field\, including the develo
 pment of biophysical models for the thermodynamics and control of biologic
 al free-energy transduction\, bioenergetics\, metabolic control analysis\,
  metabolic and signaling network modeling\, and the discovery of synchroni
 sation of glycolytic oscillations in yeast cells.\nWesterhoff has received
  numerous awards\, such as the 2018 Systems Biology Foundation Award. He i
 s a foreign member of the Italian Academy of Sciences and Fellow of the In
 ternational Society for Systems Biology.
LOCATION:SG 0211 https://plan.epfl.ch/?room==SG%0200211
STATUS:CONFIRMED
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