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Fated ?
ParadoxesAugust 4, 2013
Dr. Katie Galloway
Do your genes decide your
fate?
Infidelity gene?
Identifies-meaningless-correlations gene?
A bottom-up approach
““We are survival machines – robot vehicles blindly programmed to preserve the selfish molecules known as genes.”
– Richard Dawkins, biologist
Molecules Networks Cells Tissues Systems Organism
A Reductionist view of Biology
Environment & societyInput:
Initial conditions
Output:Fate
Molecules Networks Cells Tissues Systems Organism
Environment & societyInput:
Initial conditions
Output:Fate
Layers of design
Gene expression: Running genetic program
DNA
mRNA
protein
Promoter:Controls production RNA from DNA
pX
Epigenetics and structure of DNA
Loose packing of DNA turns on genes
Tight packing of DNA turns off genes
10,000 fold packing during cell division!
3D structure of the genome influences how sets of genes interact
DNA wrapped for tangle free, dynamic loosing and rewrapping
Gene expression: Running the program
DNA
mRNA
protein
pX
Promoter:Controls transcription of DNA to RNA
Non-coding RNA:Controls processing of mRNA into proteins
Percent of non-coding DNA increases with organism complexity
Mattick, J.S. Scientific American 2004
“Junk DNA” is not so “junky”
Mattick, J.S. Scientific American 200498% of human non-coding DNA is translated into RNA
DNA
mRNA
protein
~20,000 genes
~1,000,000 proteins
Diversity of proteins 50x > genes!
DNA
translation
Brain protein Liver protein
RNA
Not the size of your genome, but how you use it
Natural RNA control systems intervene in gene expression to direct cellular fate
DNA
transcription
pre-mRNA
editing, splicing
mRNA
translation
Brain protein Liver protein
silencing
Post-transcriptional processing
Enormous amount of information in RNA and proteins regulate cellular fate
DNA
mRNA
protein
~20,000 genes
~1,000,000 proteins
Gene expression: Running the program
DNA
mRNA
protein
Promoter:Controls transcription of DNA to RNA
pX
Non-coding RNA:Controls processing of mRNA into proteins
Proteins:Provide structure, energy production, regulation, define various cell types
Genetically identical but different
Protein N
…………………………
Protein 1
…………………………
…………………………
Heart muscle cells Brain cellsBlood cells
pX pX
Protein N
…………………………
Protein 1
…………………………
…………………………
Heart muscle cells Brain cellsBlood cells
pX pX
Levels of gene expression define cell types
< >~
Heart muscle cells Brain cellsBlood cells
Levels of gene expression define cell types
< >~
Spectrum of fate
Leve
ls o
f exp
ress
ion
Protein N
Protein 1
Synthetic control systems control gene expression to reprogram cell fate
Figure adapted from Amabile, G. & A. Meissner (2009) Trends Mol. Med. 15:59.
Simple model for proper protein folding
Native protein structure goes to lowest energy state, process runs downhill
Multi-level control for proper protein folding
Native protein structure is metastable, kinetically entrapped, guided to native fold
Important molecular control at all three levels
DNA
mRNA
protein
Promoter:Controls transcription of DNA to RNA
pX
Non-coding RNA:Controls processing of mRNA into proteins
Proteins:Provide structure, energy production, regulation, define various cell types
Molecules Networks Cells Tissues Systems Organism
Layers of design
Environment & societyInput:
Initial conditions
Output:Fate
Fast negative regulation Fast positive regulationTranscriptional regulation
A systems view of the yeast mating pathway: model cancer pathway
Figure courtesy of D.Endy. 2006
MAPK pathways: regulators of cell fate
Transmembrane receptor
MAPKKK
MAPKK
MAPK
Extracellular signal
Pathway response
Mating ProliferationDifferentiationDevelopment
InflammationApoptosis
Development
Yeast MammalianPheromone Growth factors, cytokines, cell stress
Fus3 Erk1/2 JNK p38
Implications in disease and therapeutics
Stem Cells Cancer
Hanahan, D. and R.A. Weinberg, The hallmarks of cancer. Cell, 2000. 100(1): p. 57-70
ProliferationProliferation
Differentiation
Adapted from Santos, SD et al. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol 2007
Proliferation
EGFNGF
-
Differentiation
+
Signaling = Biology’s Morse code
ProliferationProliferation
Differentiation
Adapted from Santos, SD et al. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat Cell Biol 2007
Proliferation
EGFNGF
-
Differentiation
+
Complex signal processing used to direct cell fate
Molecules Networks Cells Tissues Systems Organism
Environment & societyInput:
Initial conditions
Output:Fate
Layers of design
Life or death in response to pro-death signal is context dependent
Coordination of homeostasis in the intestine
Coordination of multiple cell types required to prevent megadeath, disaster in the intestine
Molecules Networks Cells Tissues Systems Organism
Environment & societyInput:
Initial conditions
Output:Fate
Layers of design
Stress is translated into changes in hormones, genes,
and ultimately cell fate
Stress can impair the immune system, brain function
Maternal nurturing reduces stress
Molecules Networks Cells Tissues Systems Organism
Layers of design
Environment & societyInput:
Initial conditions
Output:Fate
Molecules Networks Cells Tissues Systems Organism
Feedback changes the nature of integrated system
Environment & societyInput:
Initial conditions
Output:Fate
Molecules Networks Cells Tissues Systems Organism
Even with feedback this is still a biochemical machine
Environment & societyInput:
Initial conditions
Output:Fate
Molecules Networks Cells Tissues Systems Organism
Unless there is a mind and free will
Environment & societyInput:
Initial conditions
Output:Fate
Mind, Will
Modifying fate via behavior
Molecules Networks Cells Tissues Systems Organism
Yet, if our hope is in our will, do we have hope?
Environment & societyInput:
Initial conditions
Output:Fate
Mind, Will
For I do not do the good I want to do, but the evil I do not want to do—this I keep on doing. -Romans 7: 19
Hope in free will? Yes and no.
Molecules Networks Cells Tissues Systems Organism
God’s intervention, mercy and grace give hope
Environment & societyInput:
Initial conditions
Output:Fate
Mind, Will
God, Holy Spirit, Mercy, Grace
Molecules Networks Cells Tissues Systems Organism
God’s intervention, mercy and grace give hope
Environment & societyInput:
Initial conditions
Output:Fate
Mind, Will
God, Holy Spirit, Mercy, Grace
God is able and willing to help those who recognize their need
And Jesus said to him, “ ‘If You can?’ All things are possible to him who believes.” Immediately, the boy’s father cried out and said, “I do believe; help my unbelief.”
-Mark 9:23-24
Molecules Networks Cells Tissues Systems Organism
Quick summary: layers of design
Environment & societyInput:
Initial conditions
Output:Fate
Molecules Networks Cells Tissues Systems Organism
Quick Summary: more than a biochemical machine
Environment & societyInput:
Initial conditions
Output:Fate
Mind, Will
Molecules Networks Cells Tissues Systems Organism
Quick Summary: God designed free will & hope into our very being via our bodies, minds, and the Holy Spirit
Environment & societyInput:
Initial conditions
Output:Fate
Mind, Will
God, Holy Spirit, Mercy, Grace
A word of caution…
Jesus answered them. “Love the Lord your God with all your heart and with all your soul and with all your mind.’ This is the first and greatest commandment. And the second is like it: ‘Love your neighbor as yourself.’ All the Law and the Prophets hang on these two commandments.” -Matthew 22:37-40
Questions for reflection
1. Is the material world enough to account for the design I see in nature? If the material world is all that there is, am I satisfied knowing I am a biochemical machine?
2. For those that embrace the potential of life beyond materialism, is the will enough? Is the will enough to make you the person you should be?
3. Evidence for a personal, loving, merciful God?
4. In light of how important the mind is to knowing God and how important social interactions can be on influencing the brain, am I acting as lovingly as I can? Am I being as kind? As gracious? Am I forgiving? Am I avoiding anger, resolving conflict?
5. How will you allow the Holy Spirit to transform you?
6. How will you build your faith today?
Questions…?
