How will we crack the brain?

If you would like see things straight out of a science fiction movie, you should visit a neuroscience laboratory. Technology and science has advanced so quickly that I am not sure the public understands how advanced we are. Depending on the species, creating new transgenic animals — where you slip new genetic material into an organism — starts at ‘pathetically easy.’ During my PhD, there were days I would create the DNA for five or ten new transgenics in one go; creating the animals themselves was hardly a challenge. Light can be used as a physical force to move things around (“optical tweezers”). Scientists routinely create custom-made viruses to go forth into a chosen animal and label a precise set of neural cells. We can rain light down onto an animal to replay — or delete — memories. The recent creation of the CRISPR system allows genetic engineering to occur at unprecedented levels.

And the technology is advancing — fast. Things that seemed impossible five years ago are being commercialized right now. But for all that the brain is still largely a black box that we can prod and poke without understanding what it is actually doing, or how it got there. It begs us to ask the question: what are the directions neuroscience is heading to make a sense of this neural hydra?

The specter of past knowledge

Although no one seems to realize it now, the idea that the center of cognition and thought lies in the brain is a relatively new one. For most of human history, it was the heart that people would point to as the locus of their soul. As Carl Zimmer expertly narrates in his book The Soul Made Flesh, it was only in the 1600s, through an intense scientific effort, that the brain was identified as controlling the body. To think how many millenia of human history it took for us to realize that!

In a sense, neuroscience is both young and old. It was all the way back in 1780 that Galvani discovered that electricity caused muscles to twitch, though discovery of the chemical that allowed animals to control this process (acetylcholine) had to wait until the 1920s. But the most common neurotransmitter, glutamate, had to wait even longer. Used in perhaps 90% of neurons in the cortex, it was not nailed down as a transmitter until the 1970s. Although neuroscience has a long history, what we now take as its foundational building blocks are still stunningly new.

Because of this, the “future of neuroscience” has always been filled many “unknown unknowns”. In 1966, for instance, Marvin Minsky asked his students to attempt a simple summer project: “[construct] a significant part of the visual system.” Looking at the syllabus, it is easy to imagine how Minsky imagined he could take one simple step after another and create a skeleton of a visual system. At the time each step seemed so small — but with the benefit of hindsight each step seems more like a series of marathons. We thought it would be easy because we are intuitively visual creatures. It is so easy for us, why would it be complicated? But there is a reason that the brain spends 30% of its computational real estate in cortex on vision.

A similar attempt to guide the future came from David Marr, who wrote the groundbreaking book Vision. Marr has become something of a legend among neuroscientists: the brilliant mind that died of leukemia at the young age of 35. It would be curious to imagine the world in which Marr had survived — how far could he have gotten? — but he left behind him the skeleton of a research program that continues to be used to this day.

Marr’s levels of analysis

Nearly every question of how to advance neuroscience begins with Marr’s “levels of analysis”. The first level is computational: what is the system doing? The next is algorithmic: how does it do it? The final is implementational: what is its physical reality?

Although these questions are crystal clear, neuroscience is a particularly diverse revealing a particularly diverse set of questions. You have cognitive scientists studying how we think, you have molecular biologists studying how tiny molecules affect seemingly miniscule changes in plasticity and development, you have engineers asking how to get electrodes to decode brain activity in order to create Ghost In The Shell-style prostheses, and you have so much more. Each is studying a particular piece of a large puzzle. How are they going to do that?

The state of current knowledge

From the Cell Image Library

The past two decades has seen an explosion in tools that can dissect and record signals in the brain. Diverse sets of molecules that allow investigation of tens to hundreds of neurons simultaneously has drastically improved our spatial knowledge of the brain. Light-activated ion channels combined with genetics have allowed us to precisely label and manipulate specific types of neurons. What was once a field devoted to such physics-era concepts of electrodes and membrane voltages is slowly moving in the direction of molecular biology, with signaling cascades and custom-made viruses being the tools of the day.

What we would like to understand, though, is what are the tools of tomorrow? Where is neuroscience heading? The Future of the Brain, edited by Gary Marcus and Jeremy Freeman, collects essays from a series of neuroscientists as to the direction research is moving. Importantly for a field as variegated as neuroscience, every essay has a distinct take on what is the important direction in which to move. But several themes emerge.

Connectivity (Implementation)