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Anuska Mohapatra
BS-MS Fourth Year, Biological Sciences
In Spielberg's 1993 hit movie Jurassic Park, Ian Malcolm speaks about not tampering with the natural order of things, and just appreciating the beauty of nature as opposed to trying to control it. By the end of the movie a bunch of people get eaten by dinosaurs, but that was just a movie. However, with the genomics revolution came the development of the discipline of synthetic biology wherein researchers started making all possible attempts to create biological systems, organisms or their components, their genomes de novo or using rational design principles. We have, in fact, come to such a door and with every step forward, questions about the ethics of such projects are spawning.
The roots of synthetic biology are traced back to the postulate of existence of regulatory systems in cells assembled from molecular components by Francois Jacob and Jacques Monod in 1961 even though the invention of molecular cloning and amplification of DNA in a plasmid is believed to mark the inception of the field. Further, the discovery of restriction enzymes in 1978 allowed thorough analysis of the existing genes, at the same time, provided a scope for constructing new gene arrangements. In 2000, there were reports that scientists had successfully established synthetic biological circuits. In the period that followed studies on designing more and more circuits, bio-bricks or DNA sequences that serve as building blocks for designing and assembling larger synthetic biological circuits which could then be incorporated into living cells to construct new biological systems, were established. By 2005, researchers had developed circuits that enabled some cell-cell communication, a light-sensing circuit in E. coli and circuits capable of multicellular pattern formation, to state a few prominent ones. In 2006, researchers designed a synthetic circuit that promotes bacterial invasion of tumour cells aiding the treatment of cancer, allowing a more concrete vision of synthetic biology finding its application in therapeutic strategies to take shape.
A Computational Model of Mycoplasma mycoides
Credit : LC Woodson, PinterestA completely synthetic bacterial genome was produced in 2010 by Craig Venter and his team who, with improving ability to digitize genomic information and extensive computational and experimental paradigms, had started to wonder if they could reproduce a complete genetic system by chemical synthesising it in pieces, starting with only the digitized DNA sequence in 1995, when they had sequenced the genome of Mycoplasma genitalium, a bacterium with the smallest number of genes of all organisms whose genome had been sequenced at that time. Initially, their aim was to identify a minimal set of only the essential genes that are required for life and rebuild these genes synthetically to create a "novel" organism. They found out that more than 100 of the 485 protein-coding genes of M. genitalium can be done without when disrupted one at a time. In 2008, the full set of M. genitalium genes was constructed chemically in the laboratory with watermarks added to its DNA to identify it as synthetic and help trace its descendants back to their creator, in case they go off course. However, because M. genitalium grows at a particularly slow rate, they shifted to two faster-growing mycoplasma species, M. mycoides as donor, and M. capricolum as recipient. In 2010, the complete genome of M. mycoides was successfully synthesized from the digital record and transplanted into a genomically emptied existing recipient cell. The new cells were named JCVI-syn1.0, or Synthia and had all the expected phenotypic characteristics and were capable of continuous self-replication.
Craig Venter believed that the achievement heralded the dawn of a new era in which new life could be made to benefit humanity, starting with bacteria that churn out biofuels, soak up carbon dioxide from the atmosphere and even manufacture vaccines by incorporating additional genes. Even though he described it to be the first species to have its parents be a computer, there has been controversy over whether JCVI-syn1.0 which took US$40 million and enormous man power to produce, is a true synthetic organism. While the genome was synthesized chemically in many pieces, it was designed to match the parent genome closely and transplanted into the cytoplasm of an existing natural cell. Manufacturing DNA alone cannot ensure a viable cell: proteins and RNAs are required to read the DNA, and lipid membranes are needed for compartmentalisation. The fact that the two species used as donor and recipient belong to the same genus implied that there was still plenty of room for improvement since that might have led to reduction in potential problems which may arise due to mismatches between the proteins in the host cytoplasm and the new genome.
By 2013, scientists could engineer functional synthetic chromosome arms in yeast, and also established commercial production of artemisinin using engineered yeast strain. After further experimentation to identify a smaller set of essential genes, Craig’s team produced JCVI-syn3.0 in 2016 which contains 473 genes. Since the genome of JCVI-syn3.0 is novel, it is considered to be the first truly synthetic organism. In 2019, scientists reported the creation of the first bacterial genome entirely by a computer, named Caulobacter ethensis- 2.0, although a viable form does not yet exist.
The creation of a new synthetic viable life form in 2019, a variant of the molecular biology workhorse E. coli, by reducing the natural number of 64 codons to 59 codons instead, in order to encode all the 20 amino acids has taken the field of synthetic biology to a whole new level. Researchers at Cambridge read and redesigned the genome to replace TCG, a codon that makes an amino acid called serine, with AGC, which codes for the same amino acid. They replaced two more codons in a similar manner and around 18,000 edits later, they had replaced every occurrence of the three codons in the entire genome. The modified genetic code was then chemically synthesised and inserted into an existing E coli cell which had its DNA emptied. Known as Syn61, the new microbe with a completely synthetic and significantly altered DNA code is a little longer than usual, and grows slowly. Such designer lifeforms could be beneficial since their DNA is different making it difficult for invading viruses to take over them.
In our pursuit of knowledge, we have fashioned tools to create a living organism; an act hitherto considered so unthinkable that we worshipped who we thought could do it. The fact that we have breathed life into something is exciting as it is terrifying. We are boldly venturing into the unknown, against several complaints regarding the ethics of such practices. Several times in the past and even in the present, we have treated the delicate balance of life as something that can sustain collateral damage to allow science to progress. There are benefits, absolutely, and there may even be benefits that we don't know of yet, like finding gold while mining for iron. Even so, history has told us that humanity has not foresight to see what their creations may bring about, only the collective apathy to ignore it.
Impending doom or march towards progress, there's only one way to really find out.
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