Optogenetics: What is it? What can it do? What to expect in the future? Build an understanding from the fundamentals of life science.
Optogenetics: What is it? What can it do?
What to expect in the future? Build an understanding from the fundamentals of
life science.
This article is aimed to help you understand
the new technology of Optogenetics from the fundamentals of biology so that you
can build knowledge, rather than accumulate discrete facts. All explanations
have been included under a heading, so feel free to skip the ones you are
already familiar with. Some instances of how a conclusion was arrived at have
also been discussed through experiments so that you can understand the inner
workings of scientific laboratories. Happy learningJ
Contents:
·
Crash course in Biology
1.
Cell: The building block of
life
2.
Neuron : The building of Nervous
System
3.
Functions of the Nervous System
A. Sensory
B.
Integrative
C.
Motor
·
What is Optogenetics?
1.
Understanding Genetic
Engineering
A. What are genes?
B.
Do all cells (even neurons)
have DNA (the carrier of genes)?
·
How Optogenetics works?
I.
Step 1: Modify the neuron
v
Understand Photosynthesis
v
Understand Action potential
II.
Step 2: Insert an optical Fibre into the
brain of the animal to be studied
v
Understand Optical Fibre
·
Let’s learn!
v
Understanding electrical
signaling in the brain
v
How do neurons perceive
time?
·
How the technology is being
used today?
1.
For treating neurological
disorders
§
Parkinson’s Disease
v
Understanding Deep Brain Stimulation
(DBS)
v
Neural grafting
2.
For finding neurological cures for
mental health disorders
§
Elevated rat maze experiment
for anxiety
3.
As a memory modifying
technique
·
Why use Optogenetics?
o Story of the first road map to the brain
·
What the future holds?
§
Ethical considerations of
it’s memory modifying potential
§
Refining cures of neurological
disorders
·
Bibliography
Crash course in Biology
To understand the mechanism of optogenetics,
let’s start from the very basics of biology.
Cell: The building block of life
Cell is the basic structural and functional unit of life.
It comes from the Latin word cellula meaning small room. It is the fundamental
structural unit because all organisms can be simplified on the basis of cells.
Think of cells like Lego blocks that on being attached
together form a structure (organism). Some organisms are unicellular which
means that they have only one cell which performs all the basic functions
important for sustaining life like metabolism (Metabolism is the
process by which your body converts what you eat and drink into energy (2)) , growth (development towards functional efficiency and gradual
increase in size) and reproduction (production of new organisms from existing
organisms). Due to its self sustaining nature, cell is known as the fundamental
functional unit of life. Some organisms are multicellular, which means that
they have many cells in their body. The cells are structurally differentiated
on the basis of their location which affects their function. Human beings are
multicellular organisms.
Neuron: The Building block of Nervous
System
In multicellular organisms, there is a type of cell known
as the neuron which is the building block of the nervous system.
Image Source: cusabio.com
“The
nervous system is the major controlling, regulatory, and communicating
system in the body” (3) Any function that is performed by the body is
orchestrated by the nervous system. It gives instructions to the organs through
a network of neurons known as the nerves. “It is the center of all mental
activity including thought, learning, and memory. Together with the endocrine system, the
nervous system is responsible for regulating and maintaining homeostasis. Through
its receptors, the nervous system keeps us in touch with our environment,
both external and internal.” (3)
·
Functions
of the nervous system
In vertebrates, the nervous system is formed of brain, spinal
cord, nerves and ganglia. There are three basic functions of the nervous system:
·
Sensory (Input)
·
Integrative (Processing)
·
Motor (Output)
Thus, the functioning of the nervous system resembles the IPO
cycle of a computer.
Sensory: Collecting information (input). As it
is a communication system, it helps us to sense our surroundings by
transmitting different types of messages from sense organs. It also receives messages
from different organs so as to regulate internal functions and processes. This
is known as Sensory input.
Integrative: The processing of input comes under
the integrative function of the nervous system. The Sensory input is converted
to electrical signals known as nerve impulses and transmitted to the brain.
This input is brought together to form sensations (Meaning: a physical feeling.
All physical experiences are a result of these sensations), thoughts (electro-chemical
reactions in the brain. A single thought is a result of thousands of signals
passing through the synapses [meeting point of two nerves] in the brain) or
store the input in memory if it may be relevant for future use. Storing
important data in the brain comes under learning. Based on the result of
processing, decisions are made every moment.
Motor: On the basis of the decision taken, a
response is sent to glands or muscles. This is the motor output.
A question that rose in my mind when learning about neurons
was how do they communicate these messages to and fro from Sensory organs to Central
Nervous system and then again to Motor organs?
The discovery of the medium used by neurons takes us back in
time to the hustle and bustle of an Italian market in the midst of a lightning
storm, when scientist Luigi Galvani saw that the legs of the frogs being sold
were twitching. He concluded that electricity must be activating the nerves of
the frog. Repeating the experiment in his laboratory he found out that he was
right! So the scientific world learned that neurons communicated through
electrical signals. We literally have electricity running through our body.
What is Optogenetics?
Now that we have learnt about the basics of nervous system, let’s
understand about the upcoming technology of Optogenetics.
Opto- is a
prefix meaning vision and Genetics refers to the study heredity or inheritance
in organisms carried out by genes.
Optogenetics is a method for controlling the activity of a
neuron by using light and genetic engineering. In this process, scientists
shine light onto genetically modified neurons that are light sensitive which
changes their signals. Neurons have two functions: they can either block or
transmit the nerve impulse and shining light on them reverses their output. It
is defined as an invasive neuromodulation technique.
·
Understanding genetic engineering
Genetic engineering is
defined as “The process of changing the information in
the genetic code (the blueprints) of a living organism by adding or deleting
information. Genetic engineering is sometimes called genetic modification.” (1).
During the process of reproduction, the parent organism passes a set of codes
and instructions to specify traits to the offspring in the form of genes.
·
What are genes?
“The gene is the
basic physical unit of inheritance. Genes are arranged, one after another, on
structures called chromosomes. A chromosome contains a single, long DNA
molecule, only a portion of which corresponds to a single gene. Humans have
approximately 20,000 genes arranged on their chromosomes.” (4)
·
Do all cells have DNA (the carrier of
genes)?
“Nearly every cell in a
person’s body has the same DNA. Most DNA is located in the cell nucleus (where
it is called nuclear DNA), but a small amount of DNA can also be found in the
mitochondria (where it is called mitochondrial DNA or
mtDNA). Mitochondria are structures within cells that convert the energy from
food into a form that cells can use.” (5)
The DNA can replicate which
is an important property as each cell needs to have the exact copy of the DNA
present in the old cell. Thus, even neurons contain DNA which contain genes
that can be modified to affect their performance.
How Optogenetics works?
To perform Optogenetics,
scientists use two steps:
Step 1: Modify the neuron
Algae are aquatic organisms (most of them are unicellular
that are capable of forming oxygen through photosynthesis. Photosynthesis
is a process through which plants having the green pigment, chlorophyll, synthesize
energy in the form of glucose using water and carbon dioxide in the presence of
sunlight. Oxygen is formed as a by-product. As sunlight is crucial for the
production of glucose and energy (organisms cannot function without energy),
Algae contain a light sensitive eye spot which is a photo receptive organelle.
Photo receptive means that it is activated on receiving photons (light
particles) and organelle is a subcellular structure. This organelle contains
the light sensitive pigment channelrhodopsin. “Channelrhodopsin allows
algae to perceive water depth using light: the deeper they go, the less
light there is. These proteins control ion channels, making them capable
of generating an action potential in neurons.” (15)
“Action potentials (those electrical impulses that
send signals around your body) are nothing more than a temporary shift (from
negative to positive) in the neuron’s membrane potential caused by ions
suddenly flowing in and out of the neuron.” (16)
When blue
light shines on the eyespot of an Algae, it sends out electrical signals that make
flagella flap. Flagella is microscopic hair-like extension which is involved in
the locomotion of a cell. Scientists clone the eyespot which is capable of
sending electrical signals and genetically modify it in the neuron to be
studied.
Step 2: Insert an optical Fibre into the brain of the animal to
be studied.
“An optical fiber is a flexible, transparent
fiber made by drawing glass (silica) or plastic to a diameter slightly thicker
than that of a human hair.” (5) Data is transmitted in these wires using light
pulses. On flipping the switch on, scientists can target specific light
sensitive neurons in the brain to study how they communicate with others. This
way neurons can be studied in specific parts of the brain without affecting the
functioning of other unrelated parts.
Let’s learn!
·
Understanding electrical
signaling in the brain
Image source: Furman News –
Furman University
Electrical signaling happens
among the different and multiple neurons in the brain which determines the
brain functions. The generated electrical signals are in the order of
milliseconds. These signals are spatiotemporally encoded which means that they
depend on space (location) and time.
·
How do neurons perceive
time?
In biological system,
time is measured according to different rhythms like on the macro scale the
circadian rhythm or the
sleep-wake cycle is measured
in days or months. “At the organismal level,
daily oscillations come about through coordination of tens of thousands of
neurons situated in the suprachiasmatic nucleus (SCN).” (7) In the brain, “suprachiasmatic
nuclei are two small, paired nuclei that are found in the hypothalamus.”
(9)
Image source: National Institute of
General Medical Sciences
“Despite numbering only
about 10,000 neurons on each side of the third ventricle, the SCN is our
principal circadian clock, directing the daily cycles of behaviour and physiology
that set the tempo of our lives.” (8)
Thus, time on the biological
scale depends on rhythms or oscillations.
“Neurons are capable of telling time on the scale of tens to hundreds of
milliseconds based on their firing dynamics. The molecular clock that is born
from this, by virtue of controlling
cellular
processes, controls the organization of the three spatial dimensions. On the
other hand, in biological systems the fourth dimension, time, can be born from
the three dimensions of space.” (7)
They
are able to do this as they are located in intricate three-dimensional circuits
in the brain. “Over time, the electrical
signals form activity patterns of the brain. Actually, these patterns encode
our thoughts, skills, feelings, and memories, and thereby control the brain
function and then its resulting behavior. However, how this process is done is
unknown.” (10)
Optical, instead of
electrical, stimulation allows the study
of specific neural subsets of the brain that give rise to complex activities as
neurons respond to exciter within milliseconds.
How the technology is being
used today?
·
Treating neurodegenerative
diseases
Simulation of how the neural
circuits operate helps the scientists to understand brain activities and find
treatments of neurodegenerative diseases. “Neurodegenerative diseases occur when nerve cells in the
brain or peripheral nervous system lose function over time and ultimately die.
Although treatments may help relieve some of the physical or mental symptoms
associated with neurodegenerative diseases, there is currently no way to slow
disease progression and no known cures.” (12)
·
Parkinson’s Disease
Parkinson’s is a
neurodegenerative disease in which neurons in the brain degenerate or lose
their function and ultimately die. It is a movement disorder which results in
tremors in patients due to disorganized electrical
signals in the areas of the brain that control movement. The exact cause of this disease is unknown, however certain genes make people more susceptible
to it as they age. This disease results in the death of dopamine releasing
neurons in the brain. Current treatments include administering dopamine to
patients and deep brain stimulation (DBS).
Image: DBS for Parkinson’s Disease,
Source: Elite Ayurveda
Deep brain stimulation is a neurosurgical procedure in which doctors insert
electrodes in the concerned circuits to block irregular signals. These methods
have long lasting side effects. DBS is a time consuming process in which
doctors have to ensure that electrodes do not interfere with unrelated neurons
through a series of tests before and after the procedure to correctly locate
the target cells.
Optical stimulation through
Optogenetics allow to selectively target axons in specific regions to either
drive or inhibit an array of distinct circuit elements. After locating the
cause of the irregular signals, the cells can be replaced using neural grafting
to host connectivity. “Neural
grafting involves placing cells, either as a block of tissue or as a
suspension of dissociated neuronal cells, into a predetermined area of the
central nervous system (CNS).” (12). Thus neural transplantation has emerged as
a possible treatment of Parkinson’s disease that can be successfully done
through Optogenetics by identifying the target cells.
·
For finding neurological
cures for mental health disorders
“Optogenetics has made it
possible to determine which cells and connections across the brain are
important in defining and assembling the different features of anxiety,
including respiratory-rate changes and risk avoidance, into a distinct
behavioral state.” (13) Thus, Optogenetics is helping in finding a neurological
treatment of mental health disorders.
·
Elevated rat maze experiment
for anxiety
In the laboratory of Kay M.
Tye, experiments done on mice revealed that amygdala, part of the brain which
regulates emotions, has two different neural connections – seeking pleasure and
avoiding pain. These two tendencies describe a majority of our behaviour. In
anxiety patients, avoiding pain is a marked behaviour and over time, this
neural pathway is strengthened. In the experiment, when a mouse is kept at a
corner of the maze, it seldom explores the rest of the surroundings as they
might signal potential dangers. This is an example of avoidance of pain. When
light is shown on the target neuron, it can either transmit or block the nerve
impulse. In this experiment, the nerve impulses were blocked in the circuit
which avoids pain. When the light was switched on, the mouse freely explored
the rest of the maze. On switching the light off, the mouse retreated to the
safety of its corner.
Image: The elevated plus
maze. Measuring the time a rat spends exploring the maze versus the time spent
in the safety of closed arms. Source: Conduct Science
Thus, Optogenetics offers a
way to control the brain instantly, reversibly and without side effects.
·
As a memory modifying
technique
“Optogenetics provides even greater memory-modifying
opportunities than have previously been assumed including selective and
reversible erasure (repeated deactivation and reactivation) of a specific
memory and the retrieval of forgotten (or suppressed) memories.” (11) This new
avenue is an issue of neuroethics and debate of fundamental right and wrong,
which is discussed in the section for future implications of the technology. Optogenetics
could be used as a possible memory modifying technique (MMTs).
Why use Optogenetics?
Optogenetics was first
discovered in 2005 and is now being used in laboratories across the world.
Any technique no matter how cool it sounds must have
advantages to be utilized in scientific laboratories. After Galvani discovered
that neurons communicate through electrical signals, scientists began
experimenting on neural pathways by inserting electrodes into the brains of
humans or animals (as humans have similar brain structures to certain animals).
·
Story of the first road map of the brain
The first brain mapping was done through electrical
stimulation by Dr. Wilder Penfield, a brain surgeon who was working with
epilepsy patients. Epilepsy is “a disorder in which nerve cell activity in the
brain is disturbed, causing seizures.” (6)
In extreme cases, surgery had to be performed. Dr. Penfield
wanted to know which parts of the brain were vital so he could avoid operating
on them. He lowered electrodes into the motor areas of the brain which control
movement and passed a signal to find that one area resulted in twitching of the
finger while one caused twitching of the toe. With this experiment, he was able
to learn which part of the brain controlled different parts of the body. This
resulted in the first brain map, a road map which could tell us how the brain
communicated and controlled the body. As we have just seen, studies on the
brain required putting electrodes in the brain which could result in permanent
brain damage. Electrical stimulation causes the activation of nontarget cells
in addition to the specific cell types. Thus, scientists could not understand
clearly which cells were involved in the circuit. “For the study of
neuroscience, optical techniques are more useful tools than the pharmaceutical
and the electrical ones because of their higher speed and accuracy and less
damage to tissue. It can optionally stimulate or silence particular cell types
and neuronal circuits with millisecond temporal (related to time) accuracy.
This method allows more temporal resolution for analyzing a specific neural
circuit operation in different diseases.” (10)
Future implications of
Optogenetics.
·
Ethical considerations of its memory
modifying potential
As discussed before, optogenetic techniques can be used to
modify memory. They can blunt emotional
(traumatic) memories but also change their valences from negative to positive
and vice versa. In such cases, the issue of exploitation seems
to be of particular importance, as political regimes could use optogenetics for
their own purposes. “On one hand, this concern appears graver in the case of
changing a memory’s valence, as opposed to erasure of a specific memory, as
authoritarian governments may wish to use war veterans as propaganda tools by
imposing positive valences on extremely negative, traumatic war memories.” Thus,
people in positions of power could possibly mould the reality of people. “On the other hand, the issue of exploitation may
prove even more disturbing in cases where optogenetics is used to erase
memories of, e.g., brutal interrogations of prisoners of war.”(11) Having
control over the memory of people would give unprecedented control to powerful
people to get away with whatever they wish.
·
Refining cures of neurological
disorders
In the realm of finding cures for diseases, “the
ability to optically control neural activity opens up possibilities for the
restoration of normal function following neurological disorders. The temporal
precision, spatial resolution, and neuronal specificity that optogenetics
offers is unequalled by other available methods.” “Optogenetics is not yet
suitable for use in humans. Instead we conclude that for the immediate future,
optogenetics is the neurological equivalent of the 3D printer: its flexibility
providing an ideal tool for testing and prototyping solutions for treating
brain disorders and augmenting brain function.” (14) Thus, it could shed light
into the mystery of the black box that is our brain.
As Optogenetics is not yet used for humans, the possible
treatments of neurodegenerative diseases would provide a more refined approach
to solving these problems with little to no side effects. “Optogenetics
is quickly becoming one of the most powerful tools in neuroscience. It will not
only shed light on functional brain mapping, it will increase our understanding
of complex neural diseases potentially leading to revolutionary
treatments.” (15)
Bravo! You completed the article. I hope you could
takeaway some of what we learnt about the novel technology of Optogenetics.
Stay curious!
Bibliography :
Article references :
Wikipedia: Cell(Biology), types of cell
Introduction to the nervous system- SEER
Training (3)
Sensation meaning: Collins dictionary
What are thoughts made of? : MIT School of
Engineering
What Is
Optogenetics and How Can We Use It to Discover More About the Brain? By
frontiers for Young minds (1)
Metabolism and weight loss: How you burn
calories? – Mayo Clinic (2)
Growth Definition and Meaning: Dictionary
Reproduction: Wikipedia
Gene: Genome (4)
What is DNA? MedlinePlus Genetics
What is Algae? : LiveScience
Eyespot Apparatus: Wikipedia
Photosynthesis :National Geographic Society
Structure and types of flagella : Byju’s
Optical Fibre: Wikipedia (5)
Epilepsy: Apollo Hospitals (6)
Spatiotemporal mechanisms of life: Nature (7)
Generation of the circadian rhythms in the suprachiasmatic
nucleus: Nature (8)
Where is the suprachiasmatic nucleus? :
Neuroscientifically Challenged (9)
Optogenetics, Tools and Applications in Neurobiology
-
NCBI (10)
Optogenetics: Britannica (13)
Current and future applications of
Optogenetics – News Medical
The Memory-modifying Potential of
Optogenetics and the need for neuroethics : Springer Link (11)
Opto Definition and Meaning: Dictionary
Neurodegenerative diseases : NIEHS.NIH.GOV
Deep brain stimulation: John Hopkins Medicine
Optogenetics for neurodegenerative diseases: NCBI.NLM.NIH.GOV
Neural grafting: Today, tomorrow or never? :
Science Direct (12)
Prospects for Optogenetic Augmentation of
Brain Function: frontiers in Systems Neuroscience (14)
Optogenetics and the future of brain mapping:
Lions talk science (15)
Neuron action potentials: The creation of a
brain signal – Khan Academy (16)
Video references: