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Understand biology and engineer biology. These are the goals of synthetic biology in brief. Due to the developments in sequencing and DNA synthesis, scientists can construct genetic constructs and edit genomes. These tools answer basic research questions and provide biological applications.
But synthetic biology can never reach its full potential until artificial genome writing becomes commonplace.Chromosomes are the "hard drives" of cells. They contain most of the cell's DNA and genes. Bacteria and archaea typically have a single circular chromosome, while eukaryotes contain several linear ones. Besides genetic information, a chromosome contains structural elements. Centromers (that participate in mitosis), telomers (that have a role in maintaining linear chromosome integrity), and origins of replication (that are where DNA replication starts in circular DNA pieces) are some well-known examples.
Artificial chromosomes are chromosomes that have been fully constructed in the lab and assembled within a cell. An important note: artificial chromosomes do not mean artificial life. They function normally within cells and the DNA used is the same as the one found in nature. What is different is their origin - they don't come from a DNA template duplication - and the genetic information they carry.
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The advantages of building a chromosome align with both goals of
synthetic biology. The role of many DNA elements is unknown. By recombining, adding, or deleting DNA sequences, we can understand if a genetic part is essential and what does it do. By rewriting a genome from scratch, we can obtain a cell with specific properties - and only them! Such cells are invaluable tools for applied and fundamental research.
Current DNA technology makes the construction of short DNA pieces easy and available to most research labs, but the same cannot be said for chromosome assembly. And this is not surprising: a plasmid with a few genes contains a few thousand base pairs; a chromosome several million or billion! As a result, there are very few reported artificial chromosomes reported. The emblematic
Yeast 2.0 consortium reported the construction and assembly of
six of the yeast's chromosomes. A research group from Switzerland designed and assembled a
full bacterial chromosome with its genome minimized to the essential components; so far, they haven't managed to insert the chromosome to the organism. A
minimal bacterial cell with a synthetic genome was nevertheless announced in 2016 by J. Craig Venter Institute scientists. And recently the molecular biology workhorse, the bacterium
E. coli, got its
genome replaced by a
synthetic variant.
All these works required a huge amount of resources and faced tremendous challenges. And despite the successes, we are a long way from mastering the craft of genome writing. In a recent
article, Nili Ostrov and her collaborators in the field of synthetic genomics outline the technological advances needed to reach this goal. They list the following areas of focus: genome design, DNA synthesis, genome editing, and chromosome assembly.
Designing the
synthetic chromosome is the first step of a construction workflow. And this step is probably the most critical, as an error there will condemn the whole effort into failure. The information hidden into a genome is too vast to be handled manually. This requires computer aided design tools, which are currently under development. These tools should also predict the effect of alterations in the sequence. Ideally, design software should model how a cell will behave when the synthetic genome replaces its native one.
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Chemical DNA synthesis can provide DNA oligos a few hundred base pairs long. This is simply not good enough for chromosome synthesis. DNA synthesis will need to reach the scale of several thousand base pairs, decrease its error rate. And the assembly workflows should minimize the need of iterative cloning steps.
Genome editing is the key to generate many synthetic genome variants. Constructing a chromosome
de novo will always be laborious. Genome editing will reduce the need of reconstructing from scratch when we need to insert
a few (say, a few thousand) mutations to mimic a certain phenotype. Multiplex genome editing already exists. But instead of 20-50 edits, the techniques should allow for many thousand.
The last step of chromosome writing is the assembly of the final construct. Throwing the smaller DNA parts inside a baker's yeast cell and use its DNA repair system to stitch them up is how it's currently done, and it works well. However, the yeast has limitations on what kind of DNA sequences it can work with. For a bigger variety of constructs, we will need more hosts and transformation methods.
Genome writing will accelerate the
synthetic biology and genetic engineering applications. In medicine, engineered cells could become accurate disease models, increasing therapeutic efficiency and reducing the need for animal testing. In agriculture, plant cells with engineered genome or
plastome can guide breeding and editing efforts to increase productivity and crop robustness. In metabolic engineering, cells will produce compounds optimally. And if we want to adapt organisms for life beyond earth's boundaries, chromosome editing will let us test radical redesigns and insert novel properties.
Ostrov and collaborators write that many of the technological breakthroughs can be achieved within the next years. It sounds a bit optimistic, but let's hope we will be pleasantly surprised. Chromosome engineering has the potential to benefit all humankind, but we should be careful to not overhype the potential and promise things we can't deliver. And as the authors say - and I couldn't agree more - we have to be transparent, ethical, and share the advances globally.
I guess the ability for those that play with god (or in other words creation) are reserved for those that are either fake, fools or just plain ignorance...and they call themselves scientists.
They are nothing more than children playing which in my day age of childhood in the UK were called Meccanno Sets.
Meccano Itโs an iconic building brand with a 100-year pedigree thatโs evolved from nuts and bolts to gears, circuits and even robotics. Its newest sets incorporate maker-kid ingenuity with an โattach-anything toolโ โ which means the possibilities are almost endless.
The only difference, they are tinkering with the very fabric of human life.