Smiling young man in a brown tweed jacket and red vest
A new study by Dr Constantine Evans of Maynooth University and researchers at the University of Chicago and California Institute of Technology, published in Nature, shows how the molecules that build structures can do both the thinking and the doing.

We tend to separate the brain and muscle – the brain does the thinking; the muscle does the doing. The brain takes in complex information about the world, makes decisions, while muscle merely executes.

This brain-muscle separation has also shaped how we think about the working within a single cell; some molecules within cells are seen as 'thinkers' that take in information about the chemical environment and decide what the cell needs to do for survival; separately, other molecules are seen as the 'muscle', building structures needed for survival.  
But a new study shows how the molecules that build structures, i.e., the muscle, can themselves do both the thinking and the doing. The study, by scientists at Maynooth University, University of Chicago and California Institute of Technology was published on 17 January in Nature
"We show that a natural molecular process – nucleation – that has been studied as a 'muscle' for a long time can do complex calculations that rival a simple neural network,” said University of Chicago Associate Professor Arvind Murugan, one of the two senior co-authors on the paper. "It’s an ability hidden in plain sight that evolution can exploit in cells to do more with less; the `doing’ molecules can also do the 'thinking'."

Interacting molecular tiles recognise patterns to choose what nano-scale letter they should assemble themselves into
Copyright to this image, which describes how interacting molecular tiles recognise patterns to choose what nano-scale letter they should assemble themselves into, is Olivier Wyatt, HEADQUARTER, 2023. 

Thinking using physics 
Cells need to recognise the environment they are in and do different things to survive. For example, some combinations of molecules might indicate a time of stress that requires hunkering down while other combinations of molecules might indicate a time of plenty. But the difference between these molecular signals can be subtle – different environments might involve the same molecules but in different proportions. 

Dr Constantine Evans, Research Fellow in Professor Damien Woods' group at the Hamilton Institute in Maynooth University and lead author of the study, explained that it is a bit like walking into a house and smelling freshly baked cookies, versus smelling burning rubber. "Your brain would alter your behaviour depending on you sensing different combinations of odorful chemicals. We set out to ask if just the physics of a molecular system can do the same, despite not having a brain of any kind," he said. 
The traditional view has been that cells might be able to sense and respond in this way using molecular circuits that conceptually resemble electronic circuits in your laptop; some molecules sense, other molecules make a decision on what to do and finally 'muscle' molecules carry out an action (e.g., build a structure). 
The alternative idea explored here is that all of these tasks – sensing, decision making, response – can be accomplished in one step by the physics inherent to the 'muscle' itself. The physics involved in this study is that of "phase transitions" – think of a glass of water freezing when it hits 0 °C; first, a little fragment of ice 'nucleates' and then grows out until the whole glass of water is frozen. 
On the face of it, these initial steps in the act of "freezing" – nucleation – does not resemble 'thinking'. But this work shows that the act of freezing can "recognise" subtly different chemical combinations – e.g., the smell of oatmeal raisin cookies vs chocolate chip – and build different molecular structures in response.  
Robustness in experiments 
The authors tested the robustness of nucleation-based decision making using DNA nanotechnology, a field that Professor Erik Winfree helped pioneer. "The theory is general and should apply to any kind of molecule. But DNA lets us experimentally study nucleation in complex mixtures of thousands of kinds of molecules and systematically understand the impact of how many kinds of molecules there are and what kinds of interactions they have," explained Erik. 
The experiment revealed a few surprises – 'muscle'-based decision making was surprisingly robust and scalable. Complications not modeled in theory, such as running out of molecules during the experiment, turned out to help rather than hurt.  As a result, relatively simple experiments solved pattern recognition problems involving around a thousand kinds of molecules, nearly 10-fold larger than in earlier circuit-based approaches.  In each case, the molecules came together to build different nanometer-scale structures in response to different chemical patterns – except the act of building the structure in itself made the decision on what to build. 
The work points at a new view of computation that does not involve designing circuits but rather designing what physicists call a 'phase diagram'; e.g., for water, a phase diagram might describe the temperature and pressure conditions in which liquid water will freeze or boil. Conventionally, phase diagrams are seen as describing 'muscle'-like material properties. But this work shows that the phase diagram can also encode 'thinking' in addition to 'doing' when scaled up to complex systems with many different kinds of components. 
"Physicists have traditionally studied things like a glass of water which has many molecules but all of them are identical. But a living cell is full of many different kinds of molecules that interact with each other in complex ways. This results in distinct emergent capabilities of multi-component systems," said Dr Jackson O’Brien, who was involved in the study as a University of Chicago graduate student in physics. The theory in this work drew mathematical analogies between such multi-component systems and the theory of neural networks; the experiments pointed to how these multi-component systems might learn the right computational properties through a physical process, much like the brain learns to associate different smells with different actions.  
While the experiments here involved DNA molecules in a test tube, the underlying concepts – nucleation in systems with many kinds of components – applies broadly to many other molecular and physical systems. The authors hope this work will spur work to uncover hidden `thinking’ abilities in other multi-component systems that currently appear to merely be 'muscles'. 
The paper is titled "Pattern recognition in the nucleation kinetics of non-equilibrium self-assembly". Funding was provided by the National Science Foundation (USA), the Evans Foundation for Molecular Medicine, the European Research Council, Science Foundation Ireland, the University of Chicago Materials Research Science and Engineering Center, the Simons Foundation, and the Carver Mead New Adventures Fund. 

Dr Constantine Evans is a Research Fellow in Prof Damien Woods' group at the Hamilton Institute in Maynooth University.