Engineering the brain with light and DNA

 
 
The brain is an amazing structure that mediates all of our cognitive skills: our senses, perceptions, our emotions and feelings, our movements, what we think, what we decide and what we do. In every single moment of our lives it senses the world in multiple ways, processes information and decides, plans and executes an adequate behavior as an output.

The human brain is made of more than 80 billion neurons, specialized cells that communicate with each other at discrete points called synapses. There are around 1,000 trillion synapses in the human brain, which can pass information from one neuron to the other. To understand these neuronal connections and the circuits that they build is of upmost importance in studying the neurobiology of the brain; not only to know how it works, but also to understand how neurological and psychiatric disorders arise from abnormalities in these circuits.

Scientists are often limited in their observations by the technology available. When studying the brain, major technical challenges have to do with network complexity and fast, millisecond timescale, information processing in the nervous tissue. Optogenetics is regarded as the most recent big technological revolution in neuroscience for helping overcome these barriers, having been recently considered the method of the year by the prestigious scientific journal Nature Methods.

 

So, what exactly is optogenetics?

The term optogenetics was coined to reflect a technique that conjugates light and optics with genetic engineering. In optogenetics people use proteins that can change their structure (and therefore activity) in response to light. Light-sensitive proteins exist naturally in many organisms. For example, proteins in our retinas called opsins convert photons of light into an electrochemical signal that our brain can understand and use to reconstruct the images seen by our eyes. Other organisms, such as algae and archea, also have opsins that allow them to swim to or away from light.

The discovery of those proteins lead to the idea of putting them in neurons to precisely control their activity. Scientists isolated the DNA sequence that codes for one of these proteins, Channelrhodopsin-2 (ChR2), from algae and introduced it into neurons that don’t have it naturally. A popular way of achieving this introduction is by using an engineered virus to drag this piece of DNA into the neurons (Figure 1). Once inside the cell, the gene will be expressed, a protein will be produced and inserted in the cell membrane and voilà: now, a bolt of blue light is sufficient to activate the cell, or make it ‘fire’. All we need is a light source, like a laser or an LED, and some optical fibers to deliver it to the desired brain site (Figure 2).

Picture1
Figure 1. Channelrhodopsin-2 (ChR2), a protein from algae activated by blue light, can be used to control neuronal activity. A virus can be used to deliver the DNA sequence of ChR2 to neurons in the mouse brain.

 

Picture2
Figure 2. Neurons containing the ChR2 gene will produce the protein which is inserted in the cell membrane and can be activated by shining blue light from a laser through optical fibers.

Because the production of the protein is done inside the cell and because not all neurons use the same bits of their DNAs, scientists can choose in which neuron types the protein is expressed. This is done by engineering the virus that delivers the DNA using specific promoters that are known to be active only in the neurons of interest. As a consequence, even if the light delivered by the optical fiber is shone over a heterogeneous population of cells, only those targeted genetically to express ChR2 will be activated (Figure 3).

Picture3
Figure 3. Specific neurons can be activated within a heterogenous population over which blue light is shone by using specific promoters to genetically target ChR2 expression .

 

Nowadays people continue to develop these tools to manipulate brain activity, both to excite the neurons, as ChR2 does, and to silence them (for this purpose people use other types of light-driven proteins like Halorhodopsin and ArchT). 

How does optogenetics relate to neurological or psychiatric diseases?

The ability to manipulate specific neurons on a millisecond time scale helps understand the causal roles they play. On the top of it, optogenetics is also very promising as a way of treating diseases. An example of a pathological condition that could benefit from optogenetics is retinitis pigmentosa, a type of blindness caused by loss of retina’s photosensitive cells. In fact, by artificially expressing ChR2 in retinal cells, scientists have managed to reestablish functional vision to blind laboratory rats (1). Other possibilities include Parkinson’s and Alzheimer’s diseases, epilepsy and posttraumatic stress disorder, all  associated with pathological alterations in the activity of neurons, which can be induced or reduced to normal states using optogenetics. The same principles apply to any type of excitable cell – which includes some endocrine, muscle, and heart muscle cells – making optogenetics a revolutionary tool for engineering both body and mind.

Bibliography:
  1. Tomita H, et al. (2009) Visual Properties of Transgenic Rats Harboring the Channelrhodopsin-2 Gene Regulated by the Thy-1.2 Promoter. PLoS ONE 4(11):e7679.

 


 

Sara Matias-01

Sara Matias is an alfacinha Biomedical Engineer. At Champalimaud Foundation, she engineers neurons
that glow when a mouse behaves.

 


 

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