Science!

In between the globe trotting, I'm busy adding my two cents to the world of neuroscience and bioengineering. Here, I'll break my work down into some digestable information.

Science jargon	Everyday English
I specialize in...
Molecular and cellular neuroscience	Brain and nerve cells
High-resolution microscopy and optical system design	Designing, building, and using microscopes and laser-based systems to study brain and nerve cells
Development of optical tools for the study of neuronal activity	Making laser-controlled tools to study just how brain and nerve cells do what they do
Today, I am working in the Yonehara Lab in the Danish Institute for Translational Neuroscience (DANDRITE) at Aarhus University. I am studying a circuit in the retina, the part of your eye that converts light into the signals sent to your brain. Generally speaking, light first interacts with photoreceptor cells, called rods and cones. The light signal is sent through through two more layers of cells (bipolar cells, then ganglion cells), with signal modulation coming from a few more types of cells found in the retina. As far as scientists understand, the light signal is converted into at least twelve different parallel streams carrying different information about an image (ie. the brightness, the edges of objects, the direction of motion of objects, etc.) The brain receives these parallel streams of information and overlays them to create what we know as vision. The retinal circuit My focus is on the retinal circuit behind one of those parallel streams of visual information, the one pertaining to the direction of motion. Scientists understand that this circuit is very important in our ability to focus on a moving object. Just hold a finger in front of you, slowly move it left and right, and follow it with your eyes. You've just taken advantage of the circuit that detects the direction of motion. Sadly, not everyone can do this. Somewhere between 1 in 1000 and 1 in 6000 people suffer from a condition called congenital nystagmus, in which their eyes spontaneously move back and forth horizontally and they cannot fixate upon a horizontally moving object. You can see a video of what I'm talking about here. We don't know what causes this, and we don't have any treatment or cure. But we do know that the direction-of-motion retinal circuit is somehow involved. I'm hoping to figure out how. To better investigate this circuit, I also plan to develop some new optical tools that will make some retinal cells respond to a specific color of light. (These are cells that normally aren't light-responsive.) I can then use that color of light to control their activity. I will make other retinal cells emit fluorescent signals when they are active. I can use a microscope to record their activity. We'll be using viruses which we will engineer to deliver the genes that will make these neurons light-sensitive and fluorescence-emitting.  Using light for stimulation and recording of neuronal activity has some major advantages. It's less invasive, so the biological tissue can handle it better and stay healthier. It can also permit me to record from lots more cells at once, and to more precisely stimulate and record from them, than if I were using electrode-based technology, the traditional go-to for cellular neuroscience. The experiments that I plan to do are possible due to the advent of optogenetics over the past decade and a half. There are a lot of popular science articles out there about optogenetics, and if you're curious, I highly recommend checking one, like this piece from the American Association for the Advancement of Science. The work I do is highly technical, even by neuroscience standards. You might be curious as to how someone ends up in such a weird field. So here's some background on my professional trajectory. I began my education back at MIT, where I majored in...
Biological Engineering	A totally new engineering program, the biological equivalent of what chemical engineering is to chemistry. We studied the principles of biology and applied them to rationally design, synthesize, and/or manipulate biological systems.
Back at MIT, I began specializing in optics and spent a whole lot of time in neuroscience labs. My dream was to become a NeuroEngineer. During my senior year, I did a six-month internship in Pisa, Italy, at the Scuola Normale Superiore and the Scuola Superiore Sant'Anna, where I learned just how slow science can be and I realized that I loved living in Europe. In the fall of 2009, my love for science and living abroad fell in line when I moved to Paris, France. I was a student at the Université Pierre et Marie Curie, which awarded me my Master's and PhD for work I mostly did at Institut Pasteur in the Unit for Dynamic Neuronal Imaging.  My Master's thesis was on...
...the design and implementation of a holographic illumination system	...basically, an optical system that allowed me to shape laser light into 3-dimensional shapes of my choosing.
In other words, I built this:	And I could use it to make microscopic illumination patterns like this one of the Institut Pasteur logo:
My PhD thesis was on...
...the characterization of a novel, photo-isomerizable NMDA receptor-specific agonist for precise control of post-synaptic receptor activity	...This one's more of a mouthful and requires we take a few steps back.

It's important to understand that neurons most often communicate with each other by transmitting little chemicals, called neurotransmitters, across synapses. A synapse is a point where two neurons are nearly touching each other, in order for them to communicate. For the most part, communication across synapses is uni-directional. One neuron is always talking, and the other is always listening. One of the most common neurotransmitters is called glutamate. It has a few different receptors, or molecules sitting on the"listening" (post-synaptic) side of the synapse, waiting to bind to the neurotransmitter. One of these receptors is called the NMDA receptor.

This is a synapse, a point where two neurons come into close proximity for one-way communication. A chemical called a neurotransmitter is sent from the presynaptic neuron to the postsynaptic neuron. AMPAR and NMDAR are two types of receptors that bind the neurotransmitter, ensuring the transmission of the signal from one neuron to the next.

The NMDA receptor is found throughout the brain and it is extremely important. Problems with this receptor may underlie a whole lot of neurological problems, including Autism spectrum disorders, stroke-related neuron death, Huntington's Disease, and Alzheimer's. But still, there is a whole lot that we don't know about exactly how this receptor works. So a new tool is always useful.

At the start of my PhD, we teamed up with some chemists who were developing a new light-switchable chemical. It exists in two different shapes (isoforms), an "on" shape and an "off" shape. Light can be used to switch it "on" and "off". In its resting "off" shape, it does nothing, and won't bother neurons. In its "on" shape, it tricks the NMDA receptor into thinking it is the neurotransmitter glutamate. The NMDA receptors act like they see glutamate until we switch the chemical back "off."

The chemical I characterized for my PhD has an inactive "off" isoform (left) and an active "on" isoform (right) that interacts with the NMDA receptor much like a the neurotransmitter glutamate. This chemical, unlike glutamate, can be switched "on" and "off."

Such a chemical tool can let us carefully control exactly when, where, and how much neurotransmitter is exposed to an NMDA receptor. It's more precise than any other chemical tool available to study NMDA receptor activity in a very small area in brain tissue. It's a great way to study how the NMDA receptor works. But it took an entire PhD to test the chemical, figure out how it could best be used, and prove that it is indeed useful. If you ask me, the chemists could go back and make some more tweaks before it's ideal for studying the NMDA receptor. Still, this tool is a big advancement towards making a perfectly switchable synthetic neurotransmitter. And the work has finally been published, so if you'd like to brave some more science-y jargon, feel free to check it out the open-access Nature Communications article here!

I was really proud of this work, but I grew antsy over the years, realizing that all my time and energy was being poured into the development of a product that had no direct medical application. (At best, my chemical could be used to compare NMDA receptors in healthy and diseased brain tissue, but it won't be the cure in and of itself.) I really wanted to do work that had a more immediate real-world impact, something in neuroscience that could make people's lives better. I started getting excited by some lab work happening to cure blindness and paralysis, projects where I my lab skills could be put to use.

A couple of years later, after many phone calls, interviews, and applications, I landed myself a position in a new team studying the retina. I'll put my knowledge of optics, tool development, and cellular neuroscience to use, and hopefully learn a thing or two about disease along the way. And maybe, just maybe, one day someone's vision will be restored thanks in part to all those hours I've spent holed up in lab poring over data results and trying to optimize that next experiment. A girl can dream.