The adventures continue...

Yesterday I donned my last pair of lab gloves and pipetted my last as a postdoc. Tomorrow evening I'll leave Aarhus, Brighton bound. I have no idea what's waiting for me, but can't pretend I'm disappointed to be moving on. Join me for the next chapter of my adventures, post academia, at the new blog I'm building up: leftattherabbithole.blogspot.com

"The future ain't what it used to be"

Like any good PhD student, at the end of my degree, I found myself in somewhat of an existential crisis. What had I just spent the past four years doing? Why? Where was it taking me? And where did I want to be going?

There was no question I was overdue for a change in scenery, but what sort of change? I visited labs, attended information sessions with management consultants, spoke with pharmaceutical researchers, and even survived a three-month internship with a small biotech consulting start-up that wasn't really going anywhere. Finally, I set out to identify a research field with the potential to produce innovative clinical applications in the near future. I wanted a part of neuroscience where biotech and sci-fi-turned-reality meld. After scouring through life science start-up sites and scientific journals, I decided that the spinal cord and the retina were the places to be.

I landed a job in a retina lab, moved to Denmark, and everything seemed to be going to plan. At least, for a few months. And then things started unraveling.

European Retina Meeting (ERM) 2015 logo

The first time I started to realize I might not be in the right place was last fall at the European Retina Meeting. As I sat through talk after talk, I realized that these brilliant researchers were devoting their lives to sorting out minutiae. They were arguing over exactly how many sub-categories of a given cell type we might find in a certain layer of the retina. They were arguing about the precise significance of their patterned input and output. They were arguing about refining techniques for studying their activity. Hardly any were standing up and talking about real problems (ahem, blindness), and how their expertise might be applied to solving such problems in creative, innovative, and efficient ways. I hadn't found what I'd hoped for in this new job, and I wasn't going to find it in academia.

I felt heartbroken. I felt nauseous. I felt like a failure.

I took the Christmas holidays to reassess. Perhaps signing up for Google alerts on my research topics might keep me in the loop about exciting developments. Reading more articles might give me the know-how to finally feel that spark. Why not subscribe to neuroscience podcasts to really immerse myself? And then, in January, an email appeared in my inbox with this subject line:

Time to make a career change? Use the MIT advantage to help

It was an ad for an MIT's First Alumni Virtual Career Fair. I hesitated. What good would something like that be for someone based in Europe? Still, I figured it couldn't do any harm, so I signed up. To my surprise, there was a small consulting firm looking to send people to the UK, visa sponsorship and all. It was a chance to stay in Europe and even move somewhere where Nicolas speaks the local language, a real boon when in the market for a new job.

The next five months never felt longer. There were online tests, in-person tests, case studies, team work challenges, role plays. I felt like a circus animal jumping through hoops and nervously awaiting each round of elimination. I re-learned high school physics, I bought my first business suit, I flew to England twice, I even met the founder of the company. And then, last week, I accepted their offer.

I'm joining Newton Europe. (Yay!) Newton is a small operational consulting firm founded by three Cambridge engineers. They are in the early stages of expanding into the US, so they've begun recruiting American hires (who may one day serve as their NY-based team, emphasis on the may) and they figured MIT alumni were a good pool to start recruiting from. Their shtick, operational consulting, is different from your typical management consulting. Instead of spending most of your days in front of a computer writing reports, there will be a lot of hands-on work. In fact, all the assignments are site-based, which means I'll be living out of hotels across the UK from Monday through Friday. My projects might range from hospital operation theaters to supermarket aisles to nuclear submarine construction sites, so the job should never get too routine. The company is also results-based: if a client doesn't see at least a 10-50% operational improvement without spending an extra cent (or pence) in 2-6 months, there's no fee.

But what makes Newton so special is more than just project diversity and the results guarantee: It's the culture. This company was founded by three colleagues who were also friends. They built Newton up around the principle that the best work gets done when people feel supported, encouraged, and challenged by the colleagues, or "frolleagues," the friend-colleague hybrid term they've coined. I know I'm not on the inside yet, but concretely I know that once every two weeks, Newton sponsors a Thursday-night company-wide social event to bring everyone together, on whatever theme employees decide, from costume parties to spa nights. Every weekend, Newton employees organize optional activities, often sports-oriented. There seems to be a certain comraderie at Newton, a work hard-play hard spirit that reminds me of a place I once fondly called home: MIT.

I don't know what this next step holds, and I'm confident that leaving academia holds challenges I've yet to anticipate. And of course, no job is ever perfect. But I'm ready to give something new a try, and I'm excited to get to do it at Newton.

I used to keep a certain ironic inspirational quote up in my high school lockers that seems just the thing to close out today's post.

As the great philosopher Yogi Berra once said,

But at least it will be different.

Optogenetics: the hot new neuro tool

Optogenetics is a hot buzzword in the world of neuroscience, but it's hardly considered a household word. So what is this futuristic sci-fi-sounding topic and why should you care? I'd like to give you a taste of what it is and the potential it holds in a 3-minute summary.

Optogenetics is a novel technique which, with the flash of a light, allows us to control the electrical activity of one or many neurons. And it comes from a surprising source: pond scum.

Magnified green algae, aka pond scum

Pond scum, otherwise known as green algae, express a molecule on their surfaces that enable them to convert sunlight into an electric signal. A little more than a decade ago, some clever neuroscientists in Stanford thought to themselves, "What if we took that pond scum gene and inserted into neurons? Might we be able to then use light to control the electrical activity of neurons?" And you know what? It worked!

Some clever neuroscientists thought to themselves, "What if we took that pond scum gene for a molecule that converts light into electricity, and inserted into neurons? Might we be able to then use light to control the electrical activity of neurons?"(Image from nsf.gov)

In labs across the world, optogenetics is being applied for a variety of different applications. Neuroscientists have genetically modified many different classes of neurons to express optogenetic molecules for different experiments. This has enabled them to, all with the flick of a switch, make normally behaving mice suddenly start running in circles, relieve depression in mice, calm anxious mice, or eliminate trembling in mice suffering from Parkinsons-like symptoms. They have even used optogenetics to target and selectively erase specific memories. And that's only a few examples.

A fiber optic is implanted in a genetically-modified mouse brain in order to deliver light directly to the genetically-modified neurons expressing optogenetic molecules in order to control the activity of these neurons with light.

(This image has been widely circulated across the internet, so I don't know which source to site. Just google "optogenetic mouse" to see for yourself.)

So that's all fine, but what does tinkering with a bunch of lab rats—er, mice—mean for you and me? Well, just a couple of months ago, in early 2016, the first human underwent optogenetic therapy as part of a new clinical trial starting in the United States. This woman, who has lost her vision, hopes to have light sensitivity restored thanks to optogenetic molecules that should soon be expressed in her eye. If it works, it will be the first proof that optogenetics can be used in medicine. Potential future applications lie in many diseases and conditions across the board, including Parkinson's Disease, anxiety, chronic pain, depression, even cancer.

This may be the first you've heard of optogenetics, but I suspect it won't be the last.

News from lab

There's some good news coming from lab. For my January science update, I'm happy to fill you in on the big publication that just came from my boss Keisuke. On January 6, the journal Neuron published his latest findings in an article entitled "Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity." Quite a mouthful. So let's break this down.

"Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity"

1. What is congenital nystagmus?
This is an inherited visual disease which occurs in approximately 1 in 1500 individuals. The symptoms of the disease include a lack of optokinetic reflex, the reflex which allows to focus on objects in a moving field, and spontaneous involuntary horizontal eye oscillations. This video does a great job illustrating the condition.

Patients with this condition have severely impaired vision and can have serious social challenges stemming from the aesthetics of the condition. The severity of congenital nystagmus varies from patient to patient, and we don't quite understand why. More importantly, we don't know what causes it, and certainly not how to treat it. (*There is one technique for eliminating the spontaneous eye movements which involves cutting and re-attaching the eye muscles, and even so, we don't know why this works.)

"Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity"

2. What is FRMD7?
FRMD7 is a gene expressed in limited areas around the body, most especially in certain retinal neurons. It interacts with a membrane-associated protein, and it is especially important during development, but its activity isn't really understood. Several genetic studies have quite clearly linked mutations in this somewhat mysterious FRMD7 gene to congenital nystagmus in humans. How these mutations were causing this condition were totally unknown, until now.

"Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity"

3. What is neuronal circuit asymmetry? And why does it matter for direction selectivity?
First, let's take a look at something called direction selectivity. This refers to the ability of certain neurons in the retina to respond selectively to the movement of objects in a certain cardinal direction: up, down, left, or right. This ability of different neurons to respond to motion in one of the four directions is what allows us to detect moving objects. These neurons develop their direction selectivity after the brain tissue has significantly developed. In mice, it happens after birth, just a few days before they open their eyes. In humans, we assume that the development is similar, though we don't know for sure.

The direction selectivity is established through "circuit asymmetry," the formation of asymmetric circuit connectivity between starburst cells and their downstream signaling partners, the direction-selective (ganglion) cells. The starburst cells are a set of cells which respond more strongly when the light signal begins at their cell body and then moves out into their dendrites. (For instance, if an image signal moves from left to right across this cell, it won't elicit much of a signal from the dendrites on the left of the cell body, but it'll elicit a big signal from the dendrites to the right of body, which it passes after passing the cell body.)

A generic picture of a starburst cell which I grabbed from Psychology Today. The big spot in the center is the cell body, from which all the dendrites emanate.

These starburst cells form stronger connections with the direction-selective cells whose directional preference aligns with the preferences of the starburst cell's dendrites. We don't really know how the starburst cells know how to pick and choose the cells whose preferences align with their dendrites, but we know that they unevenly pair-up with direction-selective cells, at least in healthy individuals...

And here comes Keisuke's contribution: his original work, which just got published in Neuron, shows that mice with a mutated FRMD7 have problems with their direction-selective circuits. Specifically, their up and down direction-selective cells are just fine, but the left and right ones, the ones you'd need to focus on a horizontally-moving object and to keep your eyes from spontaneously oscillating, are all but non-existent in mice with this mutation. And remember, we know that humans with this mutation have congenital nystagmus: they can't focus on objects in a horizontally-moving scene, and their eyes oscillate horizontally. It looks like, in this case, the mouse is probably a pretty good animal model for this life-altering human disease. Through studying this mouse, we think we have the first major breakthrough in understanding this hitherto mysterious human disease.

If our extrapolations from mice to humans are correct, as they seem likely to be, then we now understand that humans with congenital nystagmus are lacking horizontal direction-selective circuits in their retina. This is a major step in understanding the neuronal circuits underlying this disease, an important step towards being able to develop a medical treatment. And more broadly, this is an important step in linking genetic mutations to problems in neuronal circuits. As Keisuke is quoted as saying in a popular science summary of his publication, "To my knowledge this is the first time that we can link a disease to a defect in neurocomputation."

I hope this was clear, and that it gives you a good idea of what that lab and I are working on.

It will be exciting to see where our investigations into the circuitry defects of congenital nystagmus will go over the next few years. Stay tuned!

Postdoc update: Finding beauty in the (very) little things

With the click of a button today, I submitted my final funding application for the fall 2015 season. It's been a rude, if unsurprising, wake-up call to what it means to be a postdoc-- so many long hours staring at screens, reworking paragraphs, and looking for just the right turn of phrase that might convince someone that my science is just the thing that will lead to that next great break-through, all the while wondering if that's even close to the truth.

I'd love to be able to share more about my project, but my hands are tied. Such is the depressing reality of science these days: it's all so cut-throat that nothing can really be shared before it's all wrapped neatly in a bow and published. Broadly, I am looking to better understand how the circuits develop in the eye (the retina) that allow us to detect motion. We've got some genes that we're particularly interested in, and some implications for better understanding the visual disease called nystagmus. I'm also working to develop tools that fall under the broad category of "optogenetics," a hot new field in science in which we design genetic systems which allow us to use light to control, manipulate, and record from neurons.

What I'm lacking in specifics, I thought I'd make up for in a little art gallery of recent scientific images. The first two are from a series I affectionately call my Starry Night collection.

Starry Night 1/2

Starry Night 2/2

These images are taken from plates of cultured cells growing densely together. I was shocked to find such beauty pop up under the microscope!

This next image is more meaningful. I call it Visualizing Vision. This is a highly magnified image of a cultured mouse retina, which closely resembles that of a human. In it, you can see a whole lot of blue amacrine cells, little intermediate cells in the chain of retinal information flow, which begins with the light-sensitive photoreceptors and goes all the way down to the ganglion cells, which form the optic nerve that sends preliminarily processed visual information along to the brain, in the form of a handful of parallel channels that each carry different aspects of the visual scene. In pink, you can see two ganglion cells, both reaching out to the hole in the top left, from which the optic nerve used to exit the retina and travel to the mouse's brain. In those pink cells, we can see axons extending toward the brain, stretching their fingers in an easily visualized goal of passing along the message as it is begins its transformation from little photons of light into that complex sensation we know as vision.

Visualizing Vision

I might be a burned-out researcher, and a postdoc filled with doubts about my future. And yet, sometimes I see images that really make me pause in amazement. I might read a thousand different charts and diagrams and textbook explanations of how the retina works, but there's just nothing quite like holding one in my hands, placing it under a microscope, and seeing its beautiful functional design first hand, knowing that I am looking at the very system that allows me to look, to perceive the visual world. I hope I was able to transmit a little bit of that wonder to you today.

Graduation Day

Many months after the fact, and hailing now from not just France but the US, Canada, and Denmark, we made it! It was fantastic to get one last (unexpected) chance to see some familiar faces from my PhD days in the Ecole des Neurosciences de Paris, as well as, of course, to see Nicolas without all that last-minute packing pre-move stress.

My PhD graduation

The French didn't quite seem to get just how a graduation ceremony is supposed to work. For one thing, having never given their high schoolers nor undergrads a graduation any sort of ceremony, they didn't realize that doctors shouldn't be wearing mortarboards. (That said, I think you would have seriously let down a lot of French grads had they shown up to find themselves given soft, squishy doctoral hats and hoods instead of the classic graduation cap and gown from the movies.)

Though they didn't quite know the ropes, to their credit, the organizers clearly put a lot of effort into making the day memorable for us. The ceremony began with a fifteen minute classical music concert performed by a full orchestra. Then a parade of professors in full regalia, including someone who seemed to be carrying some sort of scepter, marched up the aisles. After a couple of introductory talks, the keynote speaker, French Académie des Sciences member Ghislain de Marsily, gave an amusingly left-wing political call-to-action speech. He recounted his days fighting during the May '68 student rebellions which nearly toppled the French government, and he went on a brief anti-creationism rant. He argued for better gender equality, questioned how we define "the greater good," commended the class for including so many foreigners, and encouraged us to use our imaginations, creativity, and originality to go out and change the world together. (He later explained to me that he was inspired by Steve Jobs's 2005 Stanford commencement speech, though he wanted a more group-oriented, less individualistic, perspective.) He actually dared to finish his speech with a quote not only from an American president (JFK), but spoken in English. He may have been an old man in full academician regalia, but he was not bound by French tradition. Coming from the Parisians, it was a really heart-warming note on which to send off the new PhDs into the world.

And of course, no French ceremony would have been complete without a champagne reception. And so my French education is officially complete. For now.

Now the recipient of-- count 'em-- four PhDs (for just one thesis!)

A Big Decision

The big interview day (Friday, Jan. 30) came and went in a bit of a blur. I confess to having been slightly more high-strung than necessary (read: understatement) especially given that I'd had the chance earlier that same week to give a departmental seminar at the Institut de la Vision in Paris on just the same topic on which I had to interview, but while I may work well in high-pressure situations, I make no such claims about the anticipatory period. Luckily, my talk went smoothly, and the people at DANDRITE (The Danish Institute for Translational Neuroscience) were smart, friendly, and engaging. And just let me say, if ever you find yourself in Aarhus (Denmark's second largest city), do not miss out on the restaurant Nordisk Spisehus, where my interview finished over a four-and-a-half hour dinner.

I made it back to the hotel that night completely overwhelmed: the aftertaste of 5+ courses fresh on my palate, science projects swirling through my head, and a fresh job offer in my hands. I felt nauseated.

Don't get me wrong, this is exactly what I wanted! This interview could hardly have gone better. But this left me with so much to consider, and suddenly everything was very real. What direction did I really want to take for my research trajectory? I'd whittled the list down to the spinal cord and the retina as two interesting neurological systems fairly accessible for biomedical intervention and critical for quality of life. This project would put me square in the world of the retina. But was the project sufficiently medically relevant? Did I want to join a totally new team? Was I looking principally for a scientific or an engineering environment? Would this project put me on a trajectory towards possibly running my own lab, and is that really what I want? Was it even okay to respond to this offer before getting a response from a fellowship to which I'd applied for a project in Switzerland? But with the response scheduled for late March, could I possibly afford to wait? And was I willing to risk spending the next half year applying for my own independent funding for that Swiss project, especially since my PhD research project hasn't yet been published, which seriously diminishes my chances of obtaining the funding I'd need? On the other hand, was I ready to move to Denmark, a country so random that I'd never even visited it before this interview? (Note: +1 brings my countries-visited grand total to 29.)

With all this spinning through my head and my stomach, I boarded a train the following morning back to Copenhagen, where I'd flown in the day before my interview. An unsuspecting Nicolas soon met me here, only to be bombarded by all my Big Life Questions. Luckily the Questions took some interludes for exploring a new city. It was our first time in Denmark and our first weekend of traveling as just the two of us.

Our weekend in Copenhagen following my job interview in Aarhus

Gotta admit, the Danish sense of humor really had me smiling throughout the weekend.

The city was completely charming, entertainingly quirky, and colder than I'd have liked. Our weekend slipped by in a flash, but my worries didn't escape me as quickly.

Over the next couple of weeks I met with, called, and skyped professional colleagues, former classmates, friends, and family. When was I supposed to have become ready to make such a big decision about the direction in which I take my career? And how would I know if I'd made the right decision?

Finally enough was enough. I packed my bags and emailed out to accept the job offer at Aarhus University. And then I closed up my computer and ran off to a foreign country. England. (Come on, you didn't think I was going to just pack a bag, move off to Denmark, and dive straight in without some time off for traveling first?)

My highlights from London. (Sensing a theme?)

Back in Paris, I am frantically trying to wrap up the publication of my PhD work, I'm playing travel hostess for a full calendar of Airbnb renters, and I'm continuing my battles to retain the right to reside in France and receive my unemployment benefits. (I'll let you know if that ever actually happens.) And in the background, the wheels are in motion for my grand pre-postdoc travels. But more on that later.