Science
The Complexities of Cell-phones & Cellular Communication
As seemingly minute & inconsequential as they are, living cells far supercede humans in how they’re able to monitor their environments, make complex decisions, and communicate within intricate networks to coordinate responses throughout your body.
At present, scientists have successfully characterised and understood the most of the molecular “parts” which make up our biology. They’re now confounded by the next question: How do we successfully assemble these parts into complex, functional systems?
There are 3 key parts to a cell signalling network:
- Signal Perception by Receptor
- Signal Transduction
- Cellular Response
Imagine the signalling network as a construction company.
Signal Perception by the Receptor
Architects receive instructions from the client, and draws up blueprints for the company. This represents the first stage of cell signalling: The receptor. Similar to the architect, the receptor receives signals, in the form of ligands (small molecules) which bind to it, initiating a conformational change, which in turn causes a response(e.g.releasing another chemical signal, or binding to another cellular component.).
A key principle at the receptor stage is signalling specificity. In the same way that you’d want the working styles & visions of the architect & client to be compatible, the ligand should be specific to the conformation of the receptor’s active site. This ensures that even at low concentrations, the ligand will be able to efficiently bind to the receptor & initiate a response.
While we’re at it, there are typically 4 key types of signals.
- Autocrine: From within the cell
- Juxtocrine: From an adjacent cell in contact
- Pandocrine: From a nearby cell
- Endocrine: From an adjacent cell
Notice how these labels don’t describe what these signals are — they can range from peptides all the way to small inorganic molecules — but rather where they’re coming from.
Signal Transduction
Once the blueprints have been drawn up, these instructions have to be communicated to workers to actually construct the building. This is called transduction. Before we talk about what happens here, let’s talk about who’s involved.
Scientists have found that most complex signalling proteins aren’t actually that complicated; that they’re often built from simple “parts, which are often repeated in different proteins, just in different combinations. (callback to modularity!)
Downstream from the cell receptor, there are 2 key types of proteins involved:
- Catalytic Modules
- Interaction Modules
Catalytic modules deal with directly transmitting this information, like emails which send the blueprints for the building from one worker to another. A good example of this are kinases involved in the process of phosphorylation. They’re considered relay molecules, where kinases (an enzyme) attach a phosphate group to a target protein. The phosphate group acts as an “instruction” to the protein, by changing its 3D-conformation & initiating a response.
Interaction modules are slightly more complex. They act as managers & supervisors, controlling & directing the flow of information (i.e. who receives these emails). As a result, these interaction modules often bind to the catalytic modules, to control the types of responses that are initiated. This looks like interaction modules which can recognise compatible peptide sequences or that bind with specific lipid species!
Now that we’ve established the types of stakeholders involved, let’s talk about how they work together. Managers & supervisors have computer networks which allow them to email these instructions to specific individuals. What’s the comparative in cells?
A. Scaffold Proteins
Scaffold proteins act like servers, coordinating all the emails being sent and ensuring that the right workers receive them. In the cell, scaffold proteins are able to bind to 2 or more proteins, assembling these catalytic and interaction modules at the right place, and at the right times.
A really cool extension of this, is how by rearranging the scaffolding proteins, we’re essentially able to create new response pathways within the cell.
In it’s natural form, yeast possessed 2 signalling pathways that go like this:
- mating pheromone → mating pheromone receptor → scaffold proteins + interaction/catalytic modules → mating response genes
- hyper-osmotic stress → osmotic receptor → scaffold proteins + interaction/catalytic modules → osmo-response genes
Scientists were able to rearrange these scaffold proteins, which in turn rearranged the respective interaction/catalytic modules to create an entirely new input-output pathway! When put into a living cell, this pathway would now induced an osmo-response when the cell received a mating pheromone.
Realise this means that without changing the specific catalytic function of the cell, but rather rearranging different “parts”, we were able to entirely rewire its cell behaviour. Woah.
B. Allosteric switches via modular inhibition
The second method with which they interact uses many esoteric words, but I promise that it’s really quite simple. In its basal state, interaction modules will inhibit the catalytic domains through:
- Sterically blocking (e.g. altering its chemical properties) the active site of catalytic function
- Changing the proteins conformation so it’s inactive
To “activate” the protein, a ligand can bind to the receptor & disrupt the autoinhibitory function that’s happening. And this is basically what an “allosteric switch” is being able to “on”/”off” the protein’s activity by binding a ligand to its active site. An easy way to think about it is how your computer stays off in its resting state, unless you switch it on by pressing the “on” button. (“You” being a disruptive ligand)
Before we move on, an important principle that undergirds how transduction works is amplification. It’s a really simple concept — that with a single signal, we’re able to trigger a cascade of downstream reactions, creating the complexity of the signalling networks we see today.
Cellular Response
Finally, this initiates some kind of cellular response. There are way too many possible responses to go through right now, so I’ll talk about one last principle of these signalling networks: Integration.
Integration is so important because it recognises the myriad of simultaneous reactions and pathways that are occurring. For instance, this is why even if you identify a certain enzyme as perfect for a specific therapeutic agents, when put into the cell, it’s unlikely to react as expected due to “cross-talk” from other components in the cell. This is why integration is a really important factor when considering how to modify or interact with these cell signalling networks.
Application: CAR-T Cells to Fight Cancer
T-cells are a type of lymphocyte that uses special receptors on their cell surfaces to pick up and bind to specific antigens. Antigens, meanwhile, are molecules that act as “chemical identifiers” of specific pathogens, found on the surface of a pathogen or cell infected by the pathogen or floating around the body.
The receptors of these T-cells consist of
- Extracellular recognition site
- Intracellular signalling components
The idea was to create Chimeric Antigen Receptors, consisting of an antibody which recognised an antigen that was only expressed on the surface of a tumour cell. This would be combined with the intracellular signalling components of T-cells, to initiate the activation of the T-cell response.
Basically, by creating these modular synthetic receptors, researchers got T-cells to recognise specific disease antigens & redirect T-cell activity towards them. In recent years, CAR T-cell therapy has shown remarkable success in treating B-cell cancers.
As effective as they are, often CAR-T cell therapies are too strong & uncontrolled. This results in a slew of different side effects.
- Excessive release of cytokines as CAR T-cells multiply rapidly, resulting in low blood pressure & high fevers
- Destruction of B-cells
- High white blood cell activity leads to endothelial activation, where the lining of blood cells become inflamed
- Coagulation of blood
- Destruction of red blood cells (hemotoxicity)
- Neurologically adverse reactions causing swelling, seizures, headaches, etc. (neurotoxicity)
Given that we’ve found the what of our solution, these problems now lend themselves to the how of it. How exactly can we control T-cells on a more precise level, so we can specify when and to what extent they are activated?
Switchable Chimeric Antigen Receptors.
This entails layering a second switch that has to be turned “on”, in order to activate the T-cell response. They did this, by removing parts of the intracellular signalling components & isolating them within a separate component. These components are connected to modules which only heterodimerise (i.e. combine) when a specific drug is added.
The T-cell is now only activated after (i) recognising the antigen (ii) drug has been added by the physician. We’re granted much more precise control over these T-cells, both in timing & in potency of response, and they’ve been shown to more potently & serially kill these cancer cells. Really cool stuff.
Conclusion
Nature has ingeniously evolved complex regulatory circuits using simple modular proteins. And hopefully, we’re reaching a point where we can begin to understand how these regulatory circuits interact on a much more complex level, to enable us to re-engineer them to solve major problems.
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Hey, I’m Sarrah Rose! A 17 year old deeply passionate in utilising Synthetic Biology & Artificial Intelligence to solve major problems in the world today. If you enjoyed this article or would just like to chat, I’d love to hear from you:
