From the BRAIN Director: New Perspectives

BRAIN Director, Dr. John Ngai

More than two years into a global pandemic, we’ve all had to figure out new ways of living and working. For many, including myself, days of the week and months of the year have seemingly blended together into one continuous blur. I remember, just after COVID-19 hit, trying to find a way to navigate this absurdly strange time warp with one of my enduring passions: photography.

So, starting in April 2020, I set out to mark the passage of time with the lunar cycle, recording images of each full moon over the next 12 months (I only missed one due to cloudy skies). On a clear night in April, I recorded the glimmering full moon just as it rose over the treetops near my home.

moon rise
Credit: John Ngai

The image resonated with me for reasons I couldn’t immediately put my finger on, and after a while I made the connection: it mirrored one of the most iconic environmental images of all time, the fabled “Earthrise” captured by astronaut William Anders while orbiting the moon aboard the Apollo 8 spacecraft.

earth rising
Credit: NASA/Bill Anders

Why am I talking about photography and the moon? Sometimes, when we step outside of our own assumptions, new perspectives emerge. We see things in a new light. While in space circling the moon, the Apollo team was focused on a singular, pressing task: documenting the moon’s surface to help identify sites for subsequent missions to land. Orbit after orbit, it wasn’t until the fourth turn around did one of them happen to look up to see the Earth rising from behind the moon, half in mystery, half in light. Being the first humans to gain the perspective of viewing earth from the moon, “Earthrise” was a revelation.

New and different perspectives are central to revealing so much of what remains in the dark about the brain. Looking back at BRAIN Initiative research investments to date, many discoveries have offered views through new and different lenses to help understand the brain and its inner workings. I’ll mention a few here, but there are certainly others and most definitely many more to come.

It’s hard to overstate the value of being able to see, in vivid color and in very fine detail, neurons, synapses, and whole brain regions. The Nobel Prize-winning 1994 demonstration of jellyfish green fluorescent protein as a tool to label neurons in living organisms catalyzed imaging across scientific fields far beyond neuroscience. This advance prompted many scientists to adopt fluorescent labeling methods to measure neural activity, gene expression, and more. Nearly 30 years later, today we have an enormous ensemble of powerful fluorescence labeling techniques for neuroscience, many of which have grown from the BRAIN Initiative’s investment in generating new technologies. Probe-based Imaging for Sequential Multiplexing (PRISM) is one example of a method that can image multiple different proteins simultaneously within the complex network of an individual synapse. Using calcium imaging to monitor neuronal activity dates back decades and has been steadily improving over time. One current example is a new BRAIN Initiative-funded “light beads” calcium-imaging method that captures a million neurons at the same time and across a large span of the mammalian brain. With these and other currently available methods, the ability to visualize the positioning of multiple puzzle pieces at the same time certainly helps us fit them together into a larger, cohesive picture.

Just like being able to look at wider swaths of outer space paints a clearer picture of the universe, being able to image massive numbers of neurons, and deeper in the brain, expands our understanding of the universe inside our heads, as demonstrated by two recent BRAIN Initiative-funded innovations. Adaptive optics, originally developed for astronomy, helps limit imaging distortion that would otherwise hinder probing deep into the brain. A group of scientists have now created a compact adaptive optics add-on that can be retrofitted onto the microscopes neuroscientists are using now. Other BRAIN Initiative-funded techniques allow us to watch biology at the lightning-fast speed at which it actually happens. These approaches are unearthing new biological phenomena that were previously unmeasurable and thus unknowable. One example is Swept Confocally-Aligned Planar Excitation (SCAPE 2.0) microscopy, which is a way to look in real time at the firing of individual neurons in awake behaving animals, including fruit flies and mice.

New vistas can also come from data science methods that probe biological problems without the bias or subjectivity introduced by the human brain. Of course, these techniques are also useful because they can also process much more data than a person or a few people in a lab can. Artificial intelligence (AI) has the potential to facilitate a lot of very tedious work in biology, as was recently demonstrated by its ability to accurately predict how a protein folds: a time-consuming and difficult process central to drug development. Applying AI to neuroscience, BRAIN-funded investigators have developed models to understand brain computations behind thoughts. This theoretical work provides a new perspective, challenging assumptions about how the brain works and creating new questions to be asked and answered in the lab.

Seeking new perspectives is important in any walk of life: at work and yes, also at play. As I’ve often said and firmly believe, diversity of thought is vital for gaining the most angles to solve a tough problem. Not to mention, it’s refreshing to see something differently.

More than a half century ago, the Apollo astronauts didn’t see the world in front of them until one of them paused from the task at hand and looked up. Many neuroscience discoveries are waiting for us to “look up” to reveal new truths about the still-mysterious human brain. Let’s see what they will be.

With respect and gratitude,
John Ngai, Ph.D.
Director, NIH BRAIN Initiative