There’s a quote attributed to New Zealand physicist Ernest Rutherford that goes something like this: “All science is either physics or stamp collecting.” In other words, some scientists perform experiments to explain how things work, while others don’t test specific hypotheses but instead observe the natural world and take note of what they find. The latter may seem inferior, but don’t underestimate the influence of observational science; after all, biology’s greatest stamp collector was probably Charles Darwin, who planted the seeds of his theory of evolution by natural selection in his detailed field journal published in 1839: The Voyage of the Beagle.
In neuroscience, two types of stamp collections — wiring diagrams, or connectomes, and parts lists, or cell type atlases — are a major focus of time, effort, and financial investment. For example, the adult Drosophila connectome, published on a website called FlyWire.ai, is freely available for anyone to peruse. Upon its announcement, neuroscientist Sebastian Seung proclaimed in the New York Times that “mind uploading” had hit the mainstream.
The entire connectome, minimized to fit my computer screen, looks a bit like the tangled mess I pull out of my hairbrush every morning, except that each strand is color-coded to ease tracing its long, thin processes throughout the structure. Apparently, at least according to Seung, I’m staring at an uploaded mind. But what does it actually tell me?
One is immediately struck by the sheer number of neurons and connections. It’s humbling, given that when I started as a student of neuroscience, I would blindly record from spiking neurons, one by one. It felt like trying to understand a whole planet full of people by speaking to one random person at a time.
The connectome is a resource, but in and of itself it is not a specific answer to a specific question. Though it took an enormous amount of time, effort, and money to generate it, it’s not necessarily clear what breakthroughs will come of it and what those discoveries will mean for either basic science or human health. But does this matter?
Until recently, the roundworm Caenorhabditis elegans was the only organism for which a complete or near-complete connectome existed. Each of its 302 neurons is labeled, studied, and identified.
The first draft of the C. elegans connectome was published by South African biologist Sydney Brenner and colleagues in 1986. Brenner, who started studying the species in the mid-1970s and championed it as a model, received a Nobel Prize in 2002 for his work in the role of genetics in its organ development. Fittingly, his Nobel lecture was titled “Nature’s Gift to Science” — an homage to the tiny worm and the value of selecting the appropriate model organism.
Like other model organisms, C. elegans offers many practical benefits to a lab beyond its 302-neuron nervous system. It is one of the smallest and simplest organisms that is nevertheless multicellular (the fruit fly’s body, for example, comprises over half a million cells, while C. elegans has about 1,000 in total), and it is easy to maintain in bulk populations. Like other roundworms, C. elegans does not have blood or a respiratory system. It does, however, have an intestine and well-studied muscular structure. It is small — about one millimeter in length as an adult — and a large number of individuals can be kept in a single petri dish lined with agar, a jellylike substance commonly used in the lab to grow bacteria. The worms are remarkably sturdy creatures and can be purchased and stored easily in the freezer until they are thawed for use in experiments. They are particularly useful for research into the roles of genes in development, since their small number of cells are easy to track over their lifespans. On that last point, aging is a big topic of research in the species, as its lifespan of about two weeks is conveniently short.
C. elegans is also one of the simplest and smallest organisms that nevertheless has a nervous system and exhibits complex behaviors such as thermotaxis (movement toward temperature cues), chemotaxis (movement toward chemical cues), and mating, among others. It is the most primitive organism known to exhibit a lethargic state comparable to sleep, and when exposed to nicotine, it exhibits some of the classic features of addiction, like withdrawal.
The C. elegans connectome was generated using painstaking anatomical methods — essentially, slicing the microscopic worm into thin sections and imaging its cells using a powerful, high-resolution technique for preserved tissue called electron microscopy. More complete versions or variations of the worm’s connectome were published in the decades after Brenner’s initial version.
But it’s important to note here, in a truth at once frustrating and humbling, that neuroscientists still don’t fully understand how the C. elegans nervous system works despite having had a complete wiring diagram of it for decades. One of the major reasons for this is that the living nervous system, even in a worm, can behave differently — more dynamically and flexibly — than its static wiring diagram would suggest. To be fair, FlyWire gives us a lot of additional insight beyond showing connections. The Drosophila connectome it shows is not just a static map but a highly interactive and searchable database that scientists can use to quickly glean almost everything there is to know about their neuron, or brain region, of interest. We can compare the connectomes from male and female individuals, as well as from an adult brain and a larval brain, to understand how different cell types and connectivity patterns emerge throughout development or support sex-specific behaviors.
But if there’s anything we’ve learned from connectome projects thus far, it’s that stamp collections of the brain’s cells, chemicals, and connections, as comprehensive as they are, raise far more questions than answers.
Take, for example, the work of neuroscientist Eve Marder from Brandeis University. Marder spent years researching the crustacean stomatogastric ganglion (STG) — a small circuit of about 30 neurons that generates rhythmic movements in a crustacean’s digestive system in response to food, in order to move it along the digestive tract and break it down. Her work, dating back to the 1990s, shows that even with a relatively simple circuit that produces a well-defined behavior, understanding the role of each neuron and each connection is anything but straightforward.
One thing I’ve learned as a scientist, however, is that stamp collections like the connectome are worthy for precisely these reasons: They don’t give us the answers, but they help us to ask the right questions.
One major reason for this is that even in small circuits, neurons are highly interconnected in complex ways. For example, though a connectome can show synaptic connections between two neurons, scientists also need to know what type of connection it is: Neurons can exchange either chemical or electrical signals across synapses, and in some cases two neurons can share both types of connections. Neurons also can inhibit each other or be connected both directly and indirectly via other neurons, making their ultimate behavior in the circuit very hard to predict. Circuits that govern two different behaviors — in the case of the lobster STG, two different digestive movements — are not neatly segregated. A neuron’s role therefore can’t be neatly categorized by which circuit or behavior it participates in. Finally, environmental conditions like temperature can impact the timing at which neurons fire and thus the downstream consequences of their activity. All of this suggests that though we can see wiring patterns in a connectome, we can’t necessarily tell which connections are important and under what conditions.
One thing I’ve learned as a scientist, however, is that stamp collections like the connectome are worthy for precisely these reasons: They don’t give us the answers, but they help us to ask the right questions. According to longtime C. elegans researcher Cornelia Bargmann of Columbia University, who studies how the worm’s sense of smell drives complex feeding behaviors, “Every time we do an experiment, we look at those wiring diagrams and use them as a starting point for generating hypotheses.” Given the complexity of the brain, generating testable, well-reasoned hypotheses is often the hardest step.
This is a point that is not often argued to policymakers and the public in defense of stamp collecting journeys in science, which often require huge investments of money, time, and effort. When I look at the Drosophila connectome and feel that I’ve never been farther away from understanding the brain, that is exactly how I’m supposed to feel. It means I’m on the right track. Because our biggest challenge in neuroscience, if not science in general, is to find out what we don’t know.
This article Mapping the brain won’t unlock all its secrets. That’s a good thing. is featured on Big Think.