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SYNTHETIC

PHYSIOLOGY
WHAT IS SYNTHETIC
PHYSIOLOGY?

OPTOGENETIC
S

SYNTHETIC
PHYSIOLOGY

SYNTHETIC
PHYSIOLOGY
OPTOGENICS
Combination of genetic and optical methods to control
specific events in targeted cells of living tissue.

Enable the control of specific physiological processes


within those cells through exposure to light.

Introduction of fast light-activated channels and enzymes


that allow temporally precise manipulation of electrical
and biochemical events.

Need millisecond-scale temporal precision to keep pace


with the fast biological information processing.

Method of the Year in 2010


SYNTHETIC BIOLOGY
Design and construction of new biological
systems and functions not found in nature.

And the re-design and fabrication of existing


biological systems.

Interchangeable and modular DNA-encoded


parts are assembled into complex biological
circuits.
WHAT IS SYNTHETIC
PHYSIOLOGY?
Use of optogenetics to trigger and regulate
engineered synthetic biology systems.

Synthetic biology is used to design systems that


will react to optogenetics to serve a specific
purpose.

Quicker and faster method compared to gene


therapy.
Optogenetic
Control of
Mammalian
Physiology
(Theory)
The Researchers
Ye Haifeng, ETH Zurich

Marie Daoud-El Baba, IUT

Peng Ren-Wang, ETH Zurich

Martin Fussenegger, ETU Zurich & University of


Basel
Key factors in the pathway
Blue light

Melanopsin, a GTP-binding protein-coupled light


sensitive molecule

Gaq-type G Protein (Gaq), phospholipase C


(PLC), phosphokinase C (PKC)

Calmodulin, calcium sensor protein

Calcineurin, serine/threoning phosphatase

NFAT (nuclear factor of activated T-cells)


The Pathway
1) Illumination of blue light
activates a signal transduction,
leading to influx of Ca2+ into the
cell Blue light

Melanopsin

=
Trigger the opening
First signalling cascade of transient receptor
activated : Gaq, PLC & PKC potential channels,
allowing influx of
Ca2+
The Pathway
2) Intracellular Ca2+ surge activates transcription factor,
nuclear factor of activated T cells (NFAT)

activates
Ca2+ + Calmodulin (calcium sensor) Calcineurin
dephosphorylates
Activated Calcineurin NFAT
The Pathway
3) Dephosphorylated NFAT
enters the nucleus and
binds to specific promotors
(PNFAT), inducing gene
expression
Applications
Preclinial
Bioengineering
Possible cure for diabetes?
NFAT-dependent promoter: gene encoding GLP-1

GLP-1: Glucagon-like peptide 1

Physiological functions:

- Stimulates glucose-dependent insulin secretion

- Decreases glucagon secretion from the pancreas

- Promotes insulin sensitivity

- Decreases food intake by increasing satiety in brain.


Cells are engineered such that NFAT switched on
the GLP-1 gene.

Human embryonic kidney (HEK) 293 cells showed


the best transgene expression profile.

Engineered cells are implanted into the


subcutaneous tissue of diabetic mice and placed
them in a blue-lit chamber.
Activation of
Melanopsin
Diabetic mouse Blue light exposure
implanted with
engineered cells

Increase in Activation of Increase in


GLP-1 NFAT intracellular
production calcium

Glucose homeostasis
Stimulation of
insulin secretion (Decrease in blood
glucose concentration)
Possible cures for diabetes?
Study conducted by Haifeng Ye from Swiss
Federal Institute of Technology Zurich

Yes study is no cure for diabetes yet. Its a proof-


of-concept.

Surges of calcium do all sorts of things in our cells,


so the burst of blue light may have unintended
consequences.
Manufacturing of drugs that are
difficult to produce
Production of protein phamaceuticals that
impair growth or viability of their production cell
lines

Example: cancer therapeutics

Precise titration of production levels into the


viability and growth range of production cell
lines.

Light-triggered gene expression allow


production of precise amount of protein
HEK-293 cells are engineered to produce a protein
called human placental secreted alkaline
phsphatase (SEAP)

Grown in a bioreactor with blue light source


placed outside the bioreactor
By controlling the patterns and timing of the light,
it is possible create exact amounts of the protein
over a specified period of time.
PROSPECTIVE
FUTURE
Applications and Concerns
FUTURE APPLICATIONS
Alleviate symptoms of genetic diseases such as
Parkinsons.

Switch on genetic production lines that assemble


cancer-fighting drugs inside a tumour.

Treat inherited genetic disorders by switching on


a working copy of a broken or missing gene in a
carefully controlled way
CONCERNS
Synthetic biology may also lead to the synthesis
and design of harmful pathogens

Open question on whether gene therapy for


optogenetics can be safely controlled.

Mind control lead to altered personalities?