Cellosophical Explorations #2

Can a cell think? Until recently, that question would have been brushed away or rejected out of hand. Cognition was viewed as the province of brains, neurons, and complex synaptic networks. Not anymore; researchers across microbiology, biophysics, and philosophy are increasingly converging on the framework of 'basal cognition' - the notion that sensing, information processing, memory, and decision-making are fundamental properties of life itself, extending all the way down to the humble microbe.

Great, but how do we actually study unicellular cognition?

Wouldn't it be good to have a model system that serves as a lens into a really complex domain such as unicellular cognition. A model system that's already been well studied, where there's tons of experimental data - even if it wasn't collected for the purpose of studying unicellular cognition - and where new studies are relatively tractable.

As it so turns out, there is such a model system, which is bacterial chemotaxis. In fact, e. coli being ‘the most studied model organism ever’means there's tons of data that we can build upon and experimental methods that are also well understood. BTW, it's not as if people haven't thought about e. coli as a model system for studying intelligence. One of the pioneers of chemotaxis studies, Daniel Koshland, wrote a book in 1980 called "Bacterial Chemotaxis as a Model Behavioral System," which is to say that in 1980 some people were already thinking bacterial chemotaxis is a model system for studying behavior and for connecting behavioral studies with mechanistic understanding.

Forward-thinking researchers like Koshland and the eminent biophysicist Howard Berg were already recognizing that a bacterium actively exploring its environment is not merely a passive biochemical vessel. It is an active agent navigating a complex, noisy world dominated by viscous forces. Berg’s legendary three-dimensional tracking experiments demonstrated that these tiny navigators evaluate their surroundings temporally, deciding whether life is getting better or worse. To view these organisms merely as rigid, pre-programmed automatons entirely misses the profound elegance of their sensorimotor coordination.

I wonder what Koshland’s book would look like if it were written today.

For one, cognitive scientists and AI scientists/engineers aren't stuck in the old symbolic paradigm that made them look down on anyone studying bacteria as even remotely cognitive systems. And we have tons more data, and new approaches to synthetic biology that might make it plausible to study artificial cellular behavior at the same microscale that we study natural bacterial motion. We are now capable of tracking fluorescently tagged proteins as they spontaneously organize into highly ordered sensory arrays at the cellular poles. Synthetic biologists are even using engineered multicellular consortia to program Pavlovian-like associative learning[16] circuits right into the bacterial genome, proving that the ancient hardware of life is deeply programmable. The cognitive cell is no longer a fringe metaphor relegated to the realms of philosophy; it is a measurable, highly dynamic reality that continually redefines our understanding of biological computation.

The flip side of all this information is that there's too much of it, and it's not clear how one should understand the monumental stack of experimental and theoretical discoveries related to chemotaxis (let alone other aspects of e. coli biology). The theoretical literature on Chemotaxis has become a dense thicket of biophysics, non-equilibrium thermodynamics, and information theory. We now have sophisticated mathematical models detailing exactly how much free energy it costs a bacterium to maintain a high-sensitivity chemical memory, and equations quantifying the bits of information an E. coli can extract from its surroundings. Recent interdisciplinary studies even debate whether bacterial chemosensing accuracy is fundamentally limited by the physical, stochastic arrival of molecules at the receptor—a rigid boundary defined by the laws of physics - or if the limitation lies within the energetic costs of the cell's own internal processing machinery.

Here's one path through the jungle: chemotaxis offers interesting analyses at many different scales. There is the scale of the flagellar motor itself, the smallest unit of bacterial motion, which can be understood purely as a mechanical process. We understand the genetic pathways that encode for the flagellar motor and how ion flow (either Protons or Sodium) powers the flagellar motor. This motor spans only 45 nanometers in diameter yet contains a membrane-embedded stator complex (comprised of MotA and MotB proteins) and a rotor (the C-ring) that operate together like exquisitely intermeshed gearwheels. Pumping ions across the membrane drives this rotary engine, spinning a helical propeller at speeds upwards of 100 revolutions per second. Remarkably, this motor is not a static piece of hardware. It dynamically adapts to the cell's internal signaling states by physically adding or removing torque-generating stator units and switch-complex proteins on the fly, continually optimizing its sensitivity to the physical environment.

Here's a recent article in @quantamagazine.org about the flagellar motor.

One level up from the flagellar motor is the sensing-acting complex that goes from sensing chemical attractants and repellents by the bacterial cell membrane to choosing whether the flagella should turn counter-clockwise (which makes the bacterium swim forward in a straight line) or clockwise (which makes the bacterium tumble) - this is a whole organism problem which potentially offers a rich vein of cognitive analysis. Because a bacterium is physically too small to detect spatial differences in chemical concentration across its own microscopic body length, it must rely on a reliable form of short-term memory. It compares the concentration of nutrients it experiences in the present moment with the concentration it experienced a few seconds prior. This critical temporal comparison is mediated by a highly sophisticated internal network. Transmembrane methyl-accepting chemotaxis proteins (MCPs) cluster at the cell poles, acting like incredibly sensitive biological antennas. These networked arrays bind to environmental ligands and communicate directly with an intracellular histidine kinase called CheA. If the bacterium is swimming up a favorable gradient, kinase activity is suppressed, the flagellar motors remain in their default counter-clockwise state, and the cell continues its smooth forward run. If conditions deteriorate, the kinase phosphorylates a response regulator protein, CheY, which diffuses rapidly to the base of the flagellar motor, flipping the mechanical switch to a clockwise rotation and causing the cell to randomly reorient.

The true cognitive brilliance of this system, however, lies in how the cell continually resets its sensory baseline. Through the slow addition and removal of methyl groups on the receptor complex, catalyzed by the specialized adaptation enzymes CheR and CheB, the bacterium averages past environmental states. This ‘methylation state’ provides the system with integral feedback control, so that the bacterium is desensitized to the background level of a chemical, and instead, only detects the difference between the current level and the background level.

From there, we can go into even higher scale questions of several kinds. Let me mention two. The first is studying how chemotaxis (and the genetic pathways that code for it) is embedded in the larger cell cycle. After all, a bacterium moves to places where it can access higher concentrations of nutrients so that it can then reproduce, right?

How is motility related to the cell cycle? I bet someone has studied these questions, but I haven't :)

Microbiologists and systems biologists have indeed begun to untangle this question, viewing it through the lens of optimal resource allocation. Motility is highly energetically expensive. It demands massive investments of cellular resources to synthesize the dozens of different proteins required to build flagella, and it constantly drains the cell's proton motive force to keep those propellers spinning. Consequently, E. coli do not swim aimlessly if they do not have to. When cells find themselves in a nutrient-rich paradise, they rapidly suppress the expression of flagellar genes and pour their resources entirely into the massive ribosomal machinery required for rapid growth and cellular division.

Why run when you can feast?

However, as a population grows and local nutrients inevitably become depleted, the bacteria upregulate their flagellar genes, synthesize motors, and actively seek out new metabolic opportunities. Out-migration is a thing, even for bacteria.

It's also the case that Chemotaxis is an example of a two component system that has widespread use in many other aspects of bacterial and multicellular biology. What's the relationship between the other problems solved by two-component systems and the problems solved in order for Chemotaxis to happen? Are there continuities in problem space we don't know about yet? Beyond chemotaxis, two-component systems dictate how bacteria communicate with one another through quorum sensing, how they decide to enter a dormant spore state in times of extreme stress, and how they successfully navigate host immune systems during an infection. They represent a universal molecular grammar of cellular decision-making.

By looking closely at the specific evolutionary modifications that have been made to the two-component system in chemotaxis, such as the integration of a dedicated, time-delayed memory module to allow for temporal tracking, we might begin to decipher the broader, underlying rules of basal cognition. Do other two-component systems in nature utilize similar hidden memory loops to anticipate environmental changes before they happen? Could these homologous, information-processing molecular circuits be the foundational biological building blocks that eventually scaled up, over billions of years of evolution, into the complex synaptic plasticity we see in eukaryotic nervous systems?

I would like to think bacterial chemotaxis gives us a front-row seat to the origins of mind, providing a fully tractable model system where chemistry, physics, and cognition seamlessly intertwine. It forces us to subject deep questions about the nature of intelligence and mind to experimental scrutiny, and with any luck, those experimental tools will help us answer the questions too.