Synthetic Biology in a Nutshell

Not very familiar with cells, DNA, transcription, or translation? I’ve got you. If at any point you feel lost, feel free to check this quick resource

What is it though?

If you were looking for a clear, precise, and official definition of synthetic biology, I need to tell you the truth. As of now, there is none.

Isn’t this the most exciting point? Imagine working on something that is just being discovered. It’s said that biotechnology in general, is at the same point where technology was a few decades ago. When almost nobody knew what the internet was, and personal computers weren’t even a thing.

So how can we talk about something that we can’t even define? Well, in an attempt to make this easier for everybody, I’ve created my own and first definition of what synthetic biology means to me. This is a combination of many definitions that I’ve read before.

Synbio = the expansion of biotechnology as a multidisciplinary field that seeks to create new biological parts, devices, and systems, or redesign already existing ones, so that they produce a substance, or gain a new ability by combining engineering principles with biology

Biotechnology

All synbio is biotech, but not all biotech is synbio

It’s still a little unclear to me where the dividing line between biotech and synbio can be found. This is even more blurry when we specifically talk about gene editing since both involve changing an organism’s genetic code.

From what I’ve found, the difference is found in the quantity. With gene editing, you can make small changes to a large genome. For instance, the Nobel Prize-winning CRISPR is a gene-editing tool that allows you to make tiny edits in any organism’s genome. This is normally what we call gene therapy.

On the other hand, synthetic biologists insert different pieces of DNA into a receiver organism. The most common example of this is when we want to make bacteria glow. We take DNA that is originally from jellyfish and insert it into a bacteria.

Perhaps the most exciting part about the word synthetic is when we refer to the creation of novel DNA strands. This means biological components that didn’t use to exist in nature at all, but can now be used to give organisms brand-new functions.

Not only that. The holy grail of synthetic biology remains to be the creation of a new living organism… from scratch!

I don’t want to spoil this part of the article, so keep reading to find out more about this ;)

Multidisciplinary

Some of the various disciplines involved are biotechnology, systems biology, biophysics, chemical and biological engineering, electrical and computer engineering, control engineering, and evolutionary biology.

As you may have noticed, synthetic biology is the interesting combination of the messy biology and the precise engineering principles.

So why should everyone care about this? Not only because it’s going to be the next big thing, but also because anyone can get involved somehow. Are you interested in cosmetics, nutrition, energy, computation, chemistry, electricity, (or biology of course)? Synbio has something for you.

And just as we were discussing above, the great advantage of this being a new science is that almost anything could happen. Why not try to find your own application of synthetic biology?

Approaches

Synthetic Biology Levels of Abstraction

You may remember hearing that biology is not an exact science, like math, chemistry, or physics. Well, synthetic biology comes to say “why not standardize life?” This is also one of the greatest differences that you’ll find with the rest of biotech.

In this sense, the first thing we need to learn is design. More specifically, the two approaches that we take in synthetic biology are the top-down approach and the bottom-up approach.

  1. Top-down approach: from the macro to the micro-scale. Systems → Devices → Parts…
  2. Bottom-up approach: from the micro to the macro scale. DNA → Parts → Devices…

Don’t worry about these definitions right now. I promise it’ll be clearer as you read.

Standardizing Life

The reason why we think biology is not a precise science is that everything seems to happen randomly, without any precise instructions: without logic.

Conversely, engineering is all about preciseness. Everything happens because of a reason, and so each part of a problem can be explained.

Indeed, synthetic biology is built upon computing logic. So in order to understand its principles, we need to know how this way of thinking relates to the apparently messy life.

Electronics

Don’t feel intimidated by the diagram on the left. Logic is something that can be easily understood by anyone, logically 🥴.

You may think about these “logic gates” as “conditions”. Here are some analogies that can help us understand them. They all go around the concept of doing chores, where “doing chores = true” and “being lazy/not doing chores = false”.

Your mom tells you that if you…

  • Wash the car AND make your bed, you can go out with your friends: you need to do both in order to go out
  • Wash the dishes OR clean your bedroom, she’ll give you some money to go out with your friends: you can do either of them to receive the “prize”
  • Prepare your lunch XOR watch TV all afternoon, you can sleepover at your best friend’s house: you’ve been working hard so far, so you must have one false (watch TV) for you to get the reward ;)
  • Stop studying for your test NAND/NOR eat some candy, you can go on a trip with your friends!: your mom tells you to stop working so hard. You need a rest, so if you don’t do any chores, you can get a reward
  • NOT brush your teeth today, she’ll give you a dollar: this sounds like a dystopian story where the opposite happens, right?

Now that we know the basics of computer logic, we can apply that to logic circuits, where all of the previous components can be combined to create a standardized output, according to different given inputs.

Biological Part

This is supposed to be an article in which you learn the Principles of synthetic biology in a nutshell. So to go faster, we won’t go through computational circuits. Instead, we’ll dive into genetic circuits right away. Exciting, right?

Having understood the levels of abstraction (top-down and bottom-up approaches of synthetic biology), we can describe them better. Let’s take a bottom-up approach and start by defining what a biological part is.

Biological Part: it is a function; a process. Yes, it’s also a DNA/RNA sequence, but in order to call something a part in this context, we must keep in mind that it should encapsulate a function

Now, there are different parts that we can use to achieve what we want. Even when the symbols in synthetic biology may not look very similar to what we’ve just seen in computer logic, most of them have the same functions. Let’s take at some of the most common and essential parts:

Synbio symbols

Promoter: DNA sequence that’s next to where a gene. It’s where regulatory elements — proteins that help RNA get transcribed — will bind

CDS: coding region of a gene. The portion of a gene’s DNA or RNA that codes for protein

Ribosome Entry Site: RNA element that allows for translation initiation in poly-A tail dependent manner, as part of the greater process of protein synthesis

Terminator: section that marks the end of a gene or operon in genomic DNA during transcription

Operator: genetic sequence which allows “transcription proteins” to attach to the DNA sequence. The gene, or genes, which get transcribed when the operator is bound are known as the operon

Insulator: a type of cis-regulatory element known as a long-range regulatory element. Found in multicellular eukaryotes, insulators contain clustered binding sites for sequence-specific DNA-binding proteins and mediate intra- and inter-chromosomal interactions. They function either as an enhancer-blocker or a barrier, or both

Origin of Replication: sequence in a genome at which replication is initiated

Primer Binding Site: region of a DNA sequence where single-stranded primer bind to start replication

Restriction Site: located on a DNA molecule containing specific sequences of nucleotides, which are recognized by *restriction enzymes

Blunt restriction Site: The simplest DNA end of a double-stranded molecule. Both strands terminate in a base pair

5'/3' Sticky Restriction Site: an overhang is a stretch of unpaired nucleotides at the end of a DNA molecule. These can be in either strand, creating either 3' or 5' overhangs. These overhangs are in most cases palindromic. They are most often created by restriction endonucleases when they cut DNA

*RE = enzymes that can cut DNA as if they were scissors. They’re only able to recognize specific sequences

Devices

Devices are more complex assemblies of parts. In fact, they’re a collection set of parts, that implement a human-defined function.

Systems

Biological parts can be joined with each other to form devices, and devices can be joined to form: genetic circuits, plasmids, or vectors. These are concepts that we can use to refer to these systems. Some important concepts are:

This is what a common vector looks like

Vector: a DNA sequence used as a vehicle to carry foreign genetic material into another cell, where it can be replicated and/or expressed. The most commonly used vectors are plasmids.

Recombinant DNA: DNA that has been created by combining at least two fragments from two different sources. Genetic recombination (aka genetic reshuffling) is the exchange of genetic material between different organisms

Genetic LEGOs

These are the most standardized parts that we can find in synthetic biology. A BioBrick can be assembled with any other BioBrick to create a new BioBrick. It is based on restriction enzymes, but these restriction enzymes are always the same: you only need EcoRI, XbaI, SpeI, and PstI.

BioBrick parts can be assembled through a process called ‘Standard Assembly’. This includes normal cloning techniques based on restriction enzymes, purification, ligation, and transformation.

When chaining parts together, the restriction sites between the two parts must be removed, allowing the use of those restriction enzymes without breaking the new and larger BioBrick apart. In order to facilitate this assembly process, the BioBrick part itself may not contain any of these restriction sites.

Design your own biobrick!

  1. Find the sequence of your gene of interest! Tip: use the NCBI Genbank.
  2. Check your DNA sequence for the presence of BioBrick restriction sites. Even if you find them, with a little engineering, you will still be able to create your specific BioBrick.
  3. If your gene is small enough, you can order *primers with the BioBricks end sequences and use PCR to generate the desired BioBrick part. If your gene is too large for regular PCR, it is recommended to get your gene synthesized

Et voila: Your specific DNA sequence with BioBrick ends is ready to be ligated into a plasmid vector that can then be transformed into a suitable host cell. Happy construction!

Surface-level explanation
A more detailed explanation

*Primers = short, single-stranded DNA sequences used in PCR

Languages

You can tell the field has been developing quite a lot when you know that we now have more than one programming language, just to design biological circuits.

Systems Biology Markup Language (SBML): it’s a representation format for communicating and storing computational models of biological processes. It’s free and open standard. It can represent metabolic networks, cell signaling pathways, regulatory networks, infectious diseases, and many other biological phenomena.

Synthetic Biology Open Language (SBOL): it’s a proposed data standard for exchanging synthetic biology designs between software packages. It aims to develop the standard in a way that is open and democratic in order to include as many interested people as possible and to avoid domination by a single company.

Creating biological models

As mentioned above, this discipline consists of the fusion between biology and engineering. Thus, in this part of the article we’ll focus on the creation of mathematic models that reflect how our biological systems function.

To be frank, we won’t go deep into the math (mostly ordinary differential equations), but we’ll describe how this math relates to synthetic biology. So if we were to describe the process of how this works, it would be something like this:

  1. Choose a biological pathway that is involved in the end goal for your project
  2. Diagram all the protein interactions of this pathway
  3. Describe the speed of the reactions using mass action kinetics (where differential equations come in)
  • Sometimes it’s not possible to gather all reaction rates of a system
Chemical Reaction
Modeling that chemical reaction with an Ordinary Differential Equation

Synbio’s Central Dogma

Biology can be standardized after all! One of the main outcomes of this standardization is the cycle that every knowledgable person in the field follows:

Design → Build → Test → (Analyze/Learn)

Remember the biological models and programming languages, and levels of abstraction? That’s designing! The cloning methods and biobricks? That’s building. The process of actually inserting those biobricks into living things would be considered as testing, and after doing all of that, we should have learned something new, and analyzed our results.

It’s very likely that you’ll continue seeing diagrams like this to represent the DBTA cycle :)

Applications

If I explained myself well, we should already have a good understanding of the principles of synthetic biology: levels of abstraction are and what each of them means, the functions encapsulated by essential biological parts, programming biological languages, what creating a biological model means.

Now we can get to perhaps the most interesting part of this article: the real-world applications of synthetic biology. Some of these may seem a little futuristic to you, but I assure you that we’ll be seeing them in a few years from now. The bio-revolution is just beginning!

Bio-computing

It turns out that DNA can also store pretty much any information that a computer could, only it can do it for hundreds of thousands of years, and in a more efficient way. If all the information in the world was stored into DNA, it would only take the equivalent size of a shoebox (filled with DNA) to do it.

But wait… this isn’t biological computing yet 🤨. Well, you’re right. This is just the beginning of the era of biocomputing because it’s also been discovered that DNA can create electricity, solve the “Traveling Salesman Problem” problem and do what not even quantum computers can!

Bio-sensors

A biosensor refers to an engineered organism, usually a bacterium, that is capable of reporting some ambient phenomena such as the presence of heavy metals or toxins. By using the principles we’ve just talked about, synthetic biologists can design circuits that include the genes for such bio-sensors.

To prove this is not that futuristic, take a look at this mind-blowing project created by an iGEM team. They use cell-free biosensors which as paper-based test strips. Tackling the problem of date rape drug intoxications by detecting a common ingredient

XNA

In May of 2014, researchers announced that they had successfully introduced two new artificial nucleotides into bacterial DNA!

Now, this is absolutely mind-blowing! We haven’t had enough with reading, editing, and writing life. We are now creating our own life language!

Drug Delivery platforms

Synthetic biologists can now reprogram bacteria to sense and respond to a particular cancer state. The advantages of using bacteria? It can deliver the drug directly into the tumor, minimizing off-target effects.

I believe the most famous and efficient way that synthetic biology has been used to tackle cancer are engineered T cells: CAR T-cells. You can learn more about these in my article about cures and treatments for cancer.

Synthetic life

History started when humans created Gods, and it will end when humans become Gods — Yuval Noah Harari

Creating life from scratch? The holy grail of synthetic biology. Again, this isn’t something that will happen in a century. In fact, the first organism whose mother was a computer is already here. That actually happened in 2014.

Synthetic life experiments attempt to either probe the origins of life, study some of the properties of life, or more ambitiously to recreate life from non-living (abiotic).

A living, artificial cell, is defined as “a completely synthetic cell that can capture energy, maintain ion gradients, contain macromolecules as well as store information and have the ability to mutate”. Nobody has been able to create such a cell

In May 2019, researchers, in a milestone effort, reported the creation of a new synthetic (possibly artificial) form of viable life, a variant of the bacteria Escherichia coli, by reducing the natural number of 64 codons in the bacterial genome to 59 codons instead, in order to encode 20 amino acids.

Synbio 🦄s?

If you’ve read until here, you likely agree with me: the applications of synthetic biology are definitely mind-blowing. Not only because they sound advanced and futuristic, but also because we’re making real progress in making them true.

Have you wondered which would be the Facebook, Google, Apple, or Amazon of synthetic biology? Are there already big companies that are not only promising but are also giving results?

Ginkgo Bioworks

The name of a tree? Well, Ginkgo is also a synthetic biology company valued at more than $4 Billion 🤯. They are “The Organism Company”, a synthetic biology platform in which they aim to build the future of biology by standardizing processes and using the power of tech as well.

Check out their website to know more about what they do!

Ginkgo’s foundries 🙌

Twist Bioscience

They supply DNA for research and commercial applications of genetic engineering. They are now developing digital data storage applications and DNA origami-based biomaterials and nano-structures. Twist is valued at $2.7 billion!

Anyone Can Cook!

What if I told you that YOU can be a bio-hacker?

Can you imagine a world in which we can all program life, as easily as we now program websites? That would be a world free of disease and global warming, full of centenarians who look and feel like teenagers, and bio-computers!

Let me explain. If you’re reading this article, it means that you possess an electronic device. That device now allows you to communicate with people around the world, watch videos, take photos, and much more. It’s become almost essential and almost half of the population has one of these.

Now the apps in that device were coded by people just like you and me. According to a weird “tradition” in coding, those people must’ve been a bunch of young guys coding in their garages.

It’s mind-blowing to think about how technology has changed our lives lately. If you were born before 2010, you likely saw a clear technological revolution happening just in front of you. Blockbuster being eaten by Netflix, the rise of Amazon, UBER, AB&B, Instagram…

Of course, this technological revolution will keep on going. We’ll continue to have faster and lighter computers, more TikToks, and even Artificial General Intelligence.

The problem is that few people — don’t worry, you’re not one of them — have stopped to think what’s up with biology, when in fact, experts in the field like Raymond McCauley, Ray Kurzweil, and Peter Diamandis have talked about a 21st century full of life.

DIY-Bio Movement

Do-It-Yourself biology is a growing biotechnological-social movement in which individuals, communities, and small organizations study biology and life sciences, using the same methods as traditional research institutions.

As I see it, this concept encapsulates the biohacking concept. This is, DIY-Bio, is Do-It-Yourself Biohacking. But what is biohacking in the first place?

It’s amazing how similar computing and biology can actually be. You see, with the synbio principles and tools we’ve discussed earlier in the article, we’re basically able to program and hack life. To create new functions that didn’t use to exist in nature and enhance those that were already here. That’s biohacking.

Opposite to what many people may think, biohacking is becoming more accessible as time passes by. The idea behind this movement is that you don’t need to belong to a prestigious institution or have much money to learn and build life.

One of my favorite leaders in biohacking is Josiah Zayner. At first, he may appear to not know what he’s doing and to just be “breaking taboos” for the sake of doing so.

I actually like him: we need more biohackers! Imagine if technology hadn’t been democratized, and you now couldn’t be reading this article on your laptop. Well, some say that this could happen with biotech if we don’t act quickly.

iGEM

You don’t have to believe Josiah or me. You can trust iGEM: the international Genetically Engineered Machine competition, an event born in the MIT, in which people from around the world, ranging from high school students to postdocs solve world-class problems using synthetic biology.

This means that one of the best ways to start involving yourself in synthetic biology is by joining an iGEM team, or creating your own, always keeping in mind that this is a multidisciplinary field, so anyone can cook!

If you like how this sounds, I highly encourage you to check out iGEM’s website, where you’ll find all the information needed to take part, as well as some examples of past years’ amazing projects.

The “Giant Jamboree” at MIT. iGEM’s closing event

Community Labs

Another great way to start to do biohacking, without the need for prior experience or much monetary resources. Interestingly, community labs have been here for some time already.

BioCurious was founded by Raymond McCauley in 2009. Today there are more than 50 places like this around the world. All of them, encapsulating the same vision: democratization of biotechnology.

You may be thinking that 50 community labs around the world are not enough. I totally agree. If you’re feeling “biocurious”, you can take a look at this map to see if there’s one of these labs near you.

If there isn’t, I still encourage you to check out the online courses that GenSpace — another great community lab located in New York City — is offering in these pandemic times.

Biohackers at Genspace, NY

Bioinformatics

I wish I knew this when I first discovered the world of biotech. Bioinformatics is the greatest way to learn about synbio/biotech without needing anything but your computer and a wifi connection.

Actually, if you can’t wait to start your first synthetic biology project, you should know that one of the skills that you’ll develop is designing plasmids. And guess what? This can be done from your computer!

Some free programs to design plasmids are *SnapGene and Benchling. The main advantage that Benchling has is that it’s online, so you won’t have to worry about losing your work or using too much memory.

Don’t get me wrong, this can and is also used by professionals in the field, mostly to analyze genetic data, or design experiments beforehand.

*Pro-tip: download the “viewer version” of Snapgene

Successful Biohacking Projects

So all of this sounds like a utopia: anyone can cook! However, that doesn’t mean that anyone can be a chef, does it? What have biohackers actually achieved up to date?

The Open Insulin Project is an organization that has as a mission to develop open-source organisms so insulin can be produced in small-scale, by locally-based groups and can ultimately be freely available for anyone who needs it.

The RONA Vaccine Project was started by Josiah Zayner (the biohacker I was mentioning before). Sounds familiar? This is an initiative in which 3 biohackers teach, from zero, how to create your own coronavirus vaccine! 🤯

Biosafety

What can be the risks associated with people creating their own coronavirus vaccines, or simply making bacteria glow? How can we prevent that biohackers become bioterrorists? Some worst-case scenarios would include:

  • The accidental release of an unintentionally harmful organism or system
  • The purposeful design and release of an intentionally harmful organism or system
  • A future over-reliance on our ability to design and maintain engineered biological systems in an otherwise natural world

Possible responses to these concerns are:

  • Working only with Biosafety Level 1 organisms and components in approved research facilities
  • Working to educate and train a responsible generation of biological engineers and scientists
  • Learning what is possible (at what cost) using simple test systems
  • Biocontainment by: biological kill switches, disabling of the organism to replicate or pass modified or synthetic genes to offspring, use of xenobiological organisms or genetic material (XNA, see above)

What will you GROW?

If there’s one thing that I’d expect you to stay with after reading this guide, is that you build something. Actually, that you GROW something ;)

Apart from the technical side, you should know that these kinds of things aren’t difficult, nor very expensive. As in almost anything in life — both scientifically and philosophically speaking — it’s just a matter of getting started.

The XXI century will be the period with more life in history. The Biological Revolution is already here. Let’s grow together,

let’s give more life to life!

Hey! I’m Sofi, a 16-year-old girl who’s extremely passionate about biotech, human longevity, and innovation itself 🦄. I’m learning a lot about exponential technologies to start a company that impacts the world positively 🚀. I love writing articles about scientific innovations to show you the amazing future that awaits us!
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