Fated ? Paradoxes August 4, 2013 Dr. Katie Galloway Do your genes decide your fate?

Fated ?

ParadoxesAugust 4, 2013

Dr. Katie Galloway

Do your genes decide your

fate?

Fat gene?

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

No gene is an island

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…?