The Next Phase of Biological Evolution is being Engineered…by People
Researchers stare into a dish filled with oozing amoeba, and look through a microscope filled with twitching paramecia. They watch as these newly born organisms swim through their petri containers. Later, they watch clusters of stem and heart cells from the xenopus laevis frog — an entirely new life form; a biological robot — work collectively to digest and move pieces of microplastic from a small aqueous solution, and self heal when they are damaged.
As exciting as all of these microorganisms are, the scientists aren’t done. They go back to their drawing boards, iterating their algorithms, and remodeling the organisms’ morphologies. Months later, they discover an astonishing revelation on the tissue samples of a foreign organism with fire-resistant skin: it is expressed in Herring sperm DNA. They are able to identify a viable locus for retrieval and insertion, so they re-engineer the gene for compatibility in rodents, and voilá, there are fireproof rats.
After years of research and millions of genes later, geneticists are able to create an entirely functional genome that codes for general phenotypic and genotypic expressions, except promoting stable aneuploidy, so that the organism has abnormal chromosomal content, and is therefore completely gender neutral, as well as the loss of the mu receptor, as well as the functional variants of five emotionally-linked genes.
All of a sudden, the bounds of ethicality are broken, and this lab has managed to code for emotionless, genderless, consciousless, and thoughtless; the perfect human test specimen. In creating this entirely new reference of Homo sapiens, new academic studies can be conducted that push the bounds of scientific testing. Scientists are at the precipice, where these preternatural renditions of humans are subjected to cutting edge, but extremely risky, tests, from neuroscience to cancer treatments. Soon enough, new cures, vaccines, abilities, and products begin to transpire.
Subjectively speaking, does this sound like a world that you would want to be apart of?
Because it’s one that I would.
The scintillating nature of science is one that is largely constricted by our moral, ethical, and sometimes theological set of values. This diminution of academia is what prevents us from reaching optimal potential, and developing solutions that much faster.
It is the lack of accessibility to and regard for life that we can’t just create prolifically. At the heart of this issue is biology, the abstract study of life.
Now, to kill people in the name of biology would be wrong. To subject other lifeforms to testing meant for humans would be flawed. And to settle for not having another solution would be lazy. That’s why instead of doing so, we’ve begun engineering new bio-organisms.
From here on out, we’re operating on an entirely new set of standards and ideals; and from this ordeal emerges an important question:
Did you know that upcoming developmental evolution that we will experience is biological in nature?
Maybe. But did you know that it likely won’t be natural? It’s true. In fact, there is a laboratory — it’s arguably the largest synthetic biology laboratory — is working on developing the latest biological interfaces that will be the future. They’re working on engineering entirely new lifeforms.
Ginkgo Bioworks is a multi-billion dollar company that may be the factory that will stimulate biological evolution on an unprecedented scale. They’ve dubbed themselves “biology by design”, which is entirely factual. Though this possibility may seem extremely futuristic at first glance, it’s actually a prospect that’s approaching us extremely quickly. Ginkgo is developing the latest source of synthetic DNA, a core principle of synthetic biology that takes the source code of life and re-engineers it to complete certain functions.
Ginkgo’s new factory is able to rapidly develop and synthesize new organisms thanks to their autonomous laboratory, where the ideation and creative phases are left up to the researcher (that’s honestly human’s strong suit), and the materialization of these complex biological systems are literally brought to life by their machines. By being able to develop to scale, Ginkgo can work on 1000s of new living things at a time.
What follows is a comprehensive overview of this laboratory, describing how, through the scientific principles of synthetic biology, we are at the advent of a new rendition of manmade procreation.
How Life is Programmed
Biology being what is called an abstract science, one that contains various levels of abstraction, it doesn’t necessarily have a clear goal. In math, we know 2+2 = 4, in physics, we can discern that f=ma, and make that calculation. In chemistry, we know that q = m * C * ΔT. But in biology, we don’t have an array of set equations. While yes, we might sometimes use integration to find a rate of reaction (technically that’s chem), or leverage Hardy-Weinberg, or even Chi Square, but both of these concepts with set equations just result in more variables to test, or a written conclusion.
But what if we could make biology like physics, math, and chemistry? What if we could standardize biology? That’s the goal of synthetic biology — we have the ultimate goal of changing the way that physiological life works, distorting the general laws of biological systems.
The fundamental laws of life and the source code of biology is what gives rise to the possibility of creating and designing new life at a molecular level. And a the heart of that is DNA — deoxyribonucleic acid.
DNA is deoxyribose, meaning it’s a deoxygenated version of the ribose sugar. It’s deoxygenated at the 2' carbon. The lack of a reactive oxygen makes DNA more stable.
DNA is deoxyribose, so the ribo stands for the (d-)ribose sugar (a simple sugar with molecular formula C₅H₁₀O₅), and aids in making the backbone of DNA.
DNA is nucleic; it’s formed from nucleotide chains of four bases: adenine, thymine, guanine, and cytosine, or A, T, G, & C.
DNA is formed from many basic materials, but the hydrogen bonds give it a net pH lower than 7. It’s therefore an acid. DNA has a typical pH of 5–9.
From there, we get DNA, the building block of life. Our genes are made up of DNA, which define how our characteristics and behaviors are expressed. The expression is actually correlated to function, typically the formation and development of protein (which we’ll cover in a second). In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. All of the genes in an organism are called a genome.
Biology, when taken out of its abstract qualities, is much like a very simple, but wildly sensitive form of programming. Unlike in many programming languages’ syntaxes, the format of DNA only has one option to complete certain functions, and many genes (called exons) don’t code for anything. So really, scientists are working backwards. We do know some of the human genome, and it looks something like this:
though the @okezue watermark probably isn’t there, and there are about 10000000000 times more ATCGs
Ultimately, it is this code that is used to create new organisms. With each letter we change, there is a physiological effect — an edit in a gene having no effect is an effect in itself. In fact, as far as we know, over 76% of the human genome doesn’t necessarily code for anything. This is the distribution of the human genome:
- 1.1% of the genome is spanned by exons.
- 24% is in introns (coding regions of DNA).
- 75% of the genome is intergenic DNA.
Only about ¼ of our DNA is definitely coding for the construction of a protein/a very specific and vital function. The other ¾s either code for nothing, or they’re intergenic — what is considered a subset of noncoding genes at the moment — , a path of DNA sequences in between genes that may sometimes function to regulate and control genes and their expressions.
So how is protein made?
1. DNA Replication
The first step is DNA replication, where another strand of DNA is created.
To do so, we must unzip the zipper that is DNA! Fortunately, we have the enzyme helicase, which does this for us. Helicase splits DNA down the middle, forming two separate helices from DNA’s double helix.
These two separate helices are called the leading strand and lagging strands respectively. These two strands are antiparallel, meaning that they are parallel, but move in opposite directions.
The two directions are called 3' to 5' and 5' to 3'. The leading strand moves the right way from 3' to 5', while the lagging strand does the opposite.
Directions are based on the order of carbon.
It is extremely important, as enzymes are super specific about everything, so the DNA helix needs to move in the right way! Replication happens on both strands.
In the leading strand, primase, an enzyme, creates a continuous strand of RNA called a primer, which serves as a marker that binds to the end of the leading strand with the help of the DNA polymerase enzyme. This is the starting site of DNA replication.Once all of the bases are matched up (A with T, C with G), an enzyme called exonuclease strips away the primer(s). The gaps where the primer(s) where are then filled by yet more complementary nucleotides. The polymerase then takes a stroll along the leading strand, and adds the necessary nucleotide bases (A-T and C-G) where they are missing. This is called continuous, as it’s fully progressive, and it works in the 5' to 3' direction.
As for the lagging strand, RNA primers are created again, which bind at multiple points of the DNA strand. The result is a bunch of DNA chunks called Okazaki fragments, which are appended to the lagging strand in 5' to 3'.
This discontinuous replication requires that the Okazaki fragments are combined later on by an enzyme to create a continuous strand.
After DNA polymerase does it’s thing and pairs the proper bases, the exonuclease enzyme removes the primers, and then the spaces are filled with the proper As, Ts, Cs, and Gs. Then the DNA is looked over again like a test to make sure that everything is in the right place (and some mistakes will be corrected, but of course not all).
Then the DNA ligase enzyme is used to close the DNA sequences to create one DNA. With all four strands, you get two NEW DNA molecules, as you have created half-and-half new and old nucleobases. This means that the process is semi-conservative, as only ½ of it is actually new.
After you get the DNA, you move into the transcriptions process!
This is how RNA, the younger, more unstable (and oxygenated) sibling of DNA is formed.
The first step of transcription is the initiation process. This is where the RNA polymerase enzyme (the RNA version of DNA polymerase) bonds to the part of DNA called the promoter. Being at nearly the beginning of the gene, each gene has its own promoter. The RNA polymerase then creates a template to base the rest of the process on by separating the DNA strands.
The step of the transcription process is to prepare the strand by elongating it.
The created template strand of the DNA is the RNA polymerase template. It’s basically like the chapter of a book before the climax (except the words are each just A, T, C, G). RNA polymerase reads it, and starts building out RNA from the correct bases. This chain expands from 5' to 3'. However, the thymine (T) is replaced with uracil (U).
To finally stop, there is a gene sequence called the terminator that signals for the RNA that has been transcribed to be completed. The terminators cause the RNA polymerase to let go of the RNA. Now, onto the final steps.
3. Translation to create the protein.
To start, a rough particle called a ribosome (which creates proteins) surrounds the messenger RNA (mRNA) and the transfer RNA (tRNA) to be read out. Each of these RNA have a specific function depending on their prefix. This orientation is called the initiation complex.
To expand the amino acid polypeptide chain (just a string of peptide bonds which hold together amino acids), the process of elongation occurs. The mRNA are read by their codon. These are strings of three nucleotides for a sequence of the genetic code. As the mRNA is read by each codon, the amino acid corresponding to the codon is added each time (amino acids are also made of three strings, like asparagine = UUG).
For each new codon read, tRNA binds to it, the amino acid polypeptide goes onto the tRNA amino acid, and the mRNA moves over one codon over in the ribosome, which exposes another codon to repeat the process.
Finally, during elongation, the tRNA moves through parts of the ribosome called A, P, and E (aminoacyl, peptidyl, and exit) sites, which continually repeats.
Finally, to terminate, the stop codon (with code UAG, UGA, or UAA) goes into the ribosome, and then the chain is able to separate from the tRNA, effectively releasing it from the ribosome.
Because amino acids are the building blocks of proteins, the polypeptide released gives us whatever protein needed. However, this process is subject to some deformity, and the polypeptide may need to reprocess outside of the ribosome, like fix its 3D shape, or combine with others like it to make a functional protein.
Now that researchers thoroughly understand the operating system of DNA, as well as its source code, they can begin editing it using a variety of tools. They use their own proprietary software to model the changes they plan to make.
They then converge the appropriate fields: biology, engineering, and computation, to make entirely new forms of biotechnology, from generating electricity using cells (a project I’m working on 😉), to creating meat using myosatellites, to genetic engineering embryos. The different parts of a biological system can constantly be revised and changed to create a deviant whole.
The new set of principles are defined by four main principles:
Synthetic biology applies the principle of bio-design, which tells us how these four different pillars work with each other to create a final product that is functional. There are currently two perspectives:
- Progression: This is used to make smaller parts and construct new systems that ultimately create new life.
- Regression: This is using the multiple parts made in order to create one larger outcome, like an organism.
Logic consists of gates, which describe the different conditions under which something occurs! Each of these gates make up a circuit, where one or more inputs pass through a gate(s) to result in only one output.
In terms of creating new life, the inputs are genes/DNA, and the outputs are proteins!
There are so many examples where all of your friends and family start unknowingly creating computational circuits via everyday speech (no you will NOT have it). So let’s break down each of the steps in the approaches, starting with the system.
So, if we take the simple operational rules of the computers that we use today, we can input a biological part that will allow us to use operators in biological/organic systems. Let’s dive into a key technology, called a genetic circuit, in which we can use operators to code for DNA/RNA, each of which have specific functions.
In order to design functional genetic circuits, the bottom-up sequence is optimal, where we begin with the smallest components, and over time, scale to the largest one. The reason for this is because we need to define all of the different operators supported in biocomputing, which differentiates from that of electronic circuits and traditional computer logic.
So, to start, we’re going to need to break down each of these different symbols, 1 by 1. There are 18 completely different parts (21 in total):
- promoter → This is a marker that defines where RNA polymerase begins to transcribe for RNA.
- cds → a coding sequence where the gene’s DNA or RNA codes for a specific protein through amino acids.
- ribosome entry site (IRES) → the part of RNA where transcription occurs for protein creation (at the 5' end of eukaryotic mRNA).
- terminator → the signaling sequence that marks the ending of transcription on a gene/operon.
- operator → sequence that allows transcription proteins to attach to DNA.
- insulators → prevent chromatids from doing weird stuff when they’re near each other.
- ribonuclease site → active site of the enzyme that degrades RNA.
- RNA stability element → something that prevents RNAse 👆🏾 from doing it’s thing.
- protease site → active site of a protein-breakdown enzyme.
- protein stability element → something that prevents protease from doing its thing.
- replication origin → part of genome where replication started.
- primer binding site → spot on the RNA/DNA where the primer binds.
- restriction site → 6–8 base pairs of DNA that binds to a given restriction enzyme, which destroys cellular invaders.
- blunt restriction site → The simplest DNA end.
- 5' or 3' restriction site → strand of a sticky-end produced by a restriction enzyme “overhang”, and can exist on either end, which creates the 5' or 3' direction variation between restriction sites.
- 5' or 3' overhang → the phosphate for which a base ends on a restriction enzyme. If it ends on a 5' phosphate, it is a 5' overhang. If it ends on a 3' hydroxyl, it is a 3' overhang.
- signature → This is referring to the input or output of a function/class, and what it returns; a specific combination of genes or a gene that yields a certain gene expression or pattern of gene expression
- user defined (UD) → A function that contains a bunch of other assumptions/functions that perform different things. This is like a dictionary for synbio functions!
So to define a synthetic biological circuit, or a genetic circuit, we use these functions to create a biological system. The final result can look like this (not literally):
And yes, there are other parts aside from genetic circuits!
Jenga with Bio-Parts
In synbio, we have parts known as biobricks. They build up systems, which we can think of as bio-houses. Except, biobricks don’t combine like normal bricks do. They are different from Jenga; instead of stacking, two differently shaped structures can click together to form an entirely new one, and you can combine whatever you want to create something new!
This defines an important biobrick principle: biobricks can combine to form new and different biobricks. They’re the building blocks of themselves! This means that a biohouse is technically a singular biobrick. Enough confusion, let’s take a look:
Forget build-a-bear. Let’s build-a-biobrick. It’s a simple, multistep process:
- You have to determine a gene sequence that you want to use and then proceed by locating the restriction sites to begin the actual building process.
- Arrange your primers with the final biobrick sequence, then use the polymerase chain reaction or gene synthesization.
Polymerase chain reaction (PCR): A sequence of steps that expand a small DNA sample into a large one by copying it. Do: (1) denaturation of the template into single strands; (2) annealing of primers to each original strand for new strand synthesis; and (3) extension of the new DNA strands from the primers.
Just a couple of other terms you should know:
Denaturation: reshaping a protein’s/DNA’s 3D and 2D structure (except it’s primary structure). This can be done through heat or chemical stress from compounds.
Annealing: Having conducive temperatures for two separate single strands of DNA strands to come together to form the original DNA.
The biobricks utilize different cloning techniques to go from biobrick a + biobrick c to biobrick (a+c). The bricks are based on restriction enzymes EcoRI, XbaI, SpeI, and PstI, as well as other restriction endonuclease, like Bacillus amyloliquefaciens (BAMHI).
Restriction endonuclease: protein (enzyme) made by bacteria that cleaves DNA and destroys foreign substances, like viruses
Biological devices are actually quite simple. They’re just a bunch of parts that work collectively to define a full function. We have a lot of devices in the human body, from our cells, to our nerves, to our enzymes that make up different reaction complexes. You can think of it as a car dealership. The parts are assembled on the assembly line, and then they make the devices, which constitute the functionality and form of the final car (the system).
As we already know, parts + parts = devices, devices + devices = systems. And their derivatives are the materials that we get. Systems include genetic circuits, plasmids, or vectors.
Ok, so we’ve gotten parts down. But then, I just knowledge-bombed with plasmids and vectors. Let’s break these down too, because they’re simple!
Well, the two are actually related. A plasmid is a circular bundle of DNA found inside of the cell. To get a recombinant plasmid, you digest part of the plasmids genetics with a restriction enzyme, and insert a new target gene with the enzyme DNA ligase. Then the plasmid will spread its new genetic code with all other gene-containing structures in the cell, like chromosomes.
On the other hand, a vector can be a plasmid. These are exploding cars with DNA inside that transmit a new genetic structure to the rest of the cell for molecular cloning. Vectors can be viral, meaning they’re spread quickly using a virus. This is a common tool in the field of optogenetics, where the brain is gene-edited by a viral vector, so neurons can be light stimulated, for example.
From here, the bigger question becomes “how do we create life using what has been learned?”
So, back to the premise of this post — Ginkgo Bioworks is going Umbrella Academy style and is building synthetic life. But how do they do it?
We can rule out Terrigen Crystals, magic, and basically any other sci-fi thing, and go back to DNA. Just like in genetic engineering techniques used in synthetic biology where specific loci are tweaked and edited, Ginkgo leverages this principle and makes entirely proprietary code, which makes an entirely novel organism.
Much of the positions at Ginkgo are extremely unconventional; they deal with head’s on design, and microbe engineering. Very specific, and not very physical-work intensive in a sense. They require skill, understanding, and capability, but the machines are the one’s realizing the creative visualization of the research teams, who are laying out the blueprint by deciphering genes, and using their findings to create new genetic codes that have never existed before.
Ginkgo has looked at millions of organisms:
They take numerous samples and identify their productive capabilities. When engineering new organisms, or editing the existing ones that nature has provided, the conclusive focus is almost always on manipulating how these different organisms are capable of coding for the production of proteins or other molecules. Ginkgo also examines their physiological characteristics.
Some organisms produce hydrophobic and fatty substances such as lipids. Some organisms excel at producing proteins, vitamins, or energy. Some organisms grow, reproduce, and heal spontaneously and extremely quickly. Some microorganisms are extremely receptive to genetic modifications. The more organic references, the more possibilities.
The possibilities that are presented to the team at Ginkgo is thanks to their design-build-test workflow, which describes how they implement a standard three step process to standardize biology, and build new DNA codons:
- They start by designing what they want to create. This includes what the optimal function would be, the morphological structure of the organism, alongside its possible propensities. If they’re looking at the already existing biology of nature (of which there is a lot), they find what ingredients and/or changes are necessary. It’s like creating a burger — which in biotech can sometimes be literal. Look at Impossible Foods, for example.
- After understanding what parts are needed, the scientists begin to build by putting them together, allowing the machines to automatically sequence the different builds in their system, catalog it, and construct it based on programming autonomously. Having machines means they don’t have to rely on their hands to build their designs, allowing them to focus and perfect their creative efforts. They can test 6,000 organisms and DNAs at a time, as opposed to 100 or 200. Less manpower + more tech-power= better solution (or at least in this case).
- Finally, they test their organism. They draw conclusions based on their research question and hypotheses and determine whether or not they’ve gotten what they wanted. If they don’t, it’s still a win. That’s the best part about research, especially biology research. You never lose, because the goal is to learn. You learn with both failure and success. After we test, we analyze, and then it’s back to the drawing board (literally — design).
They can literally design DNA on the computer and have it synthesized by a machine through a technology called high throughput DNA synthesis. The name says it all. This is an extremely fast and efficient method of generating DNA, and PCR can be used to stretch the sample that much further by cloning it to get millions of copies. Through this, the researchers at Ginkgo take the first step of designing new lifeforms.
At Ginkgo, they do things to scale. While in a typical research lab, a fellow may handle 10–20 different samples, and one apparatus for research. At Ginkgo’s institution, they test and fabricate entire genetic libraries at a time, taking in 1,000–10,000 genes in a single sitting.
They can then screen the genes all together to determine the optimal candidates for their experimentations. Once they have their top genetic candidates for their projects, they can then collate them to generate the best possible biochemical pathway for an organism.
After they have designed a full pathway, they start iterating on it with different and more improved strains, or versions of these pathways. Armed with on-site “protein engineers”, the design and engineering leads can begin modifying their proteins for more efficient or specific pathways, they can start hacking away with engineering tools like CRISPR or TALENs, using DNA’s intrinsic repair mechanisms to their advantage.
Once they set up the organism’s pathways for a specific task, it’s up to the data scientists and machine learning/AI experts to determine their shapes and constructions using the supercomputers available, and also manage the machines to ensure that they’re working properly.
After generating the DNA and inserting them into strains, the organisms are grown inside of fermentors. The fermentation process is the biological capability to convert one substance into another. The fermentation process is typically what is used to grow the organisms, along with some growth media and it typically progresses something like this:
The Ginkgo lab process is not typical. It’s unconventional, but it’s inventive, and fosters creativity at its most engrossing level. The leading laboratories across the world look nothing like how Ginkgo’s does, and most of them aren’t kicking the idea of synthetic life into high gear.
Ginkgo is thinking big, trying to solve some of the world’s most difficult problems, such as protecting beehive entrance ways, to biological robots, to growing luxury crops in underdeveloped countries to enhance their markets, all with biology.
Just 50 years ago, when we learned to understand biology’s source code, creating new organisms from scratch would have been considered an inane, and far fetched dream. But the future is now.
What would have been considered science fiction, is now just science.
And this science is all around us. It’s in the wind, in animals, in materials, and everywhere we step. When we begin to change, edit, and enhance this science, we begin changing nearly everything around us, revolutionizing our way of life. They say that life is a gift, and it is. But the real benefaction to me is what we can do with it.
Before you go…
Thanks so much for being curious and actually reading through this article. It was a lot of fun to make, research, and develop, so I’m glad you made it through. For more on Ginkgo and biotechnologies, read my Medium, and/or check out their website and this video. If you’re from Ginkgo Bioworks, I would love to engage with you further, and feel free to fact check this article even more! If not, I would still love to talk and I hope you enjoyed this article.
My name’s Okezue, a developer and researcher obsessed with learning and building things, especially when it involves any biology or computer science. Check out my socials here, or contact me: email@example.com.
I write something new every day/week, so I hope to see you again soon! Make sure you comment, and leave some claps on this too — especially if you liked it! I sure enjoyed writing it!
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