Build a Synthetic Biological Circuit at Home

The trillions of cells in your body have the ability to detect and respond to various stimuli and inputs, coordinate tasks, build structures, and adjust to their environment.

What if we could program cells to react to custom inputs and thus produce desirable outputs?

Well, it’s possible with synthetic biological (or genetic) circuits!

As an important part of biological computing, synthetic biological circuits mimic the logic functions performed in electronic circuits with cells instead of computers. Implementing logic circuits in cells could expand the horizons of synthetic biology and unlock the computing potential of cells.

Synthetic biological circuits can allow us to better understand and engineer cells by altering cellular functions, inducing responses to environmental conditions, or influencing cellular development.

By designing biological circuits, synthetic biologists can manipulate cellular information-processing systems for the detection and remedial of disease states, the production of useful substances, and the self-assembly of new tissues.

A genetic regulatory network (GRN) is a natural biological circuit, in which molecular regulators interact in the cell to govern the gene expression levels of mRNA and proteins.

This regulation of gene expression determines the function of the cell.

While DNA, RNA, protein, and their complexes can act as molecular regulators, structural proteins, enzymes, and transcription factors can be produced by the mRNA molecules. Structural proteins will provide certain structural properties, enzymes will catalyze biochemical reactions, and transcription factors will activate or inhibit particular genes. The transcription factors must bind to the promoter region to initiate or prevent the production of another protein.

A simple diagram of the control process of a GRN I made, inspired by https://upload.wikimedia.org/wikipedia/commons/thumb/d/df/Gene_Regulatory_Network_2.jpg/720px-Gene_Regulatory_Network_2.jpg

A GRN can be modelled as a Boolean network like this:

  1. Each gene, input, and output is represented by a node in a graph where arrows connect nodes where a relation exists
  2. Each node in the graph can either be on or off (like 1 and 0 in a binary system!)
  3. If the gene is on, it is expressed. If inputs and outputs are off, they’re present.
  4. The new state of a node is a Boolean function of the prior states of the nodes with arrows pointing towards it.

In the image below, (A) is a sketch-plot that provides a static view of various biological components and their interactions, yet fails to display the dynamic properties of the system. (B) rather shows the Boolean network model as a logical circuit to model the regulatory interactions between the various components and (C) depicts the dynamics of the network as a directed graph, in which every node shows the possible assignment of each component.

https://ars.els-cdn.com/content/image/1-s2.0-S200103701930460X-gr1.jpg

Many synthetic biological circuits are now inspired by the lactose operon, which was the first natural biological circuit to be studied. Also known as the lac operon, it’s necessary for the transport and metabolism of lactose in E. coli and other bacteria that reside in the digestive tract of animals. The lac operon has 2-part control mechanisms, with which it can guarantee that enzymes are only produced when necessary and energy isn’t needlessly expended.

We might forget how truly complex and powerful biological information processors are as we become increasingly dependent on electronic ones.

A logic gate is a simple circuit that compares one or more inputs, hence producing a single, outgoing output.

Check out my article for more on logic gates in classical computers, Basics of Biological Computing.

Synthetic biologists will use many tools to computationally simulate synthetic and natural biological circuits.

Cello is a framework that automatically designs circuits by making use of a library of Boolean logic gates and creates a DNA sequence which encodes the desired circuit. Users can describe a circuit function with Verilog, a hardware description language, upload a user constraints file with the organism of choice, gate technology, and valid operating conditions, and specify the sensors and actuators.

Another tool for the modeling, analysis, and design of genetic circuits is iBioSim, developed by the Chris Myers research group at the University of Utah. iBioSim is capable of modeling metabolic networks, cell-signalling pathways, and other biological systems and visualizing multi-cellular and spatial models.

TinkerCell is popular for network design and simulation, allowing synthetic biologists to design new circuits and simulate them. Although it’s no longer being developed actively, TinkerCell can still be downloaded and the tutorials can be followed.

Check out the Applications of the Synthetic Biology Open Language (SBOL) for more software tools.

Cells could someday react to signal toxic surroundings and react by activating pathways to degrade the present toxins. Thanks to synthetic biological circuits, biological computers might sense inflammatory signals in the body and consequently, produce and release a specific treatment.

A circuit has already been designed to induce cell death with activated Ras oncogenes, proteins that are linked to cancers. Mutations of an oncogene change its function and create the malignant properties that cancers need to grow and spread. By selectively killing cancerous cells when they first manifest themselves, we could entirely avoid the onset of symptoms!

On April 3rd 2020, a team led by the University of Washington School of Medicine revealed the creation of artificial proteins that act as molecular logic gates. These de novo protein logic gates could respond to exhaustion signals during CAR T-cell therapy and prolong the activity of T-cells in the fight against cancer.

“Longer-lived T cells that are better programmed for each patient would mean more effective personalized medicine,” says Zibo Chen, a UW graduate student.

A synthetic biology company building tools to program cells is Asimov, which focuses on engineering therapeutics and developing next-generation medicines. Using genes, Asimov is building new biological systems and using computational tools, the company is designing and modelling complex biophysical systems. Christopher Voigt is Asimov’s co-founder and James Collins is its scientific advisor!

Synthetic biological circuits have been proven fruitful for metabolic engineering and synthetic biology, successfully producing pharmaceuticals and biofuels. As our knowledge of natural genetic circuitry grows and our understanding of , entire algorithms from control theory could someday be applied

A toolbox of circuitry pieces to create pathways for effective feedback systems?

We might soon expect a future in which the design of biological circuits resembles the design of integrated circuits in electronics…

Check out the Notion document for this project here.

Thanks for reading Build a Synthetic Biological Circuit at Home! If you enjoyed my article or would like to connect, you can find me on LinkedIn.

computational biology & biological computing. ammiellewb.com