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Synthetic genome

Synthetic genome

A synthetic genome created through chemical synthesis which is able to function when inserted into cells. The process of producing a synthetic genome is also called genome writing.

Prokaryotic genomes

The first fully synthetic bacterial genome was reported in 2010 by Daniel Gibson and his team at the J. Craig Venter Institute. The synthesized genome of Mycoplasma mycoides consisted of 1.1 million base pairs. The genome was transformed into the closely related species Myocoplasma capricolum. After cell division, the bacteria contained many proteins characteristic of M. mycoides. The group added four ‘watermark sequences’ to distinguish the synthetic genome from the original genome. In 2016, the Venture Institute team generated a reduced Mycoplasma genome that was reduced in size by the removal of hundreds of genes. In both cases the synthetic DNA was assembled and hosted in yeast cells (Saccharomyces cerevisiae) where recombination and genome-editing methods are highly efficient, before being transformed into Mycoplasma cells. 



A synthetic genome of the bacteria Escherichia coli was generated and reported in Nature in May 2019 by a research group led by Jason Chin at the Medical Research Council Laboratory of Molecular Biology (M.R.C. laboratory) in Britain. The genome of the bacteria has been recoded, meaning the three letter genetic code was changed to another one that codes for the same amino acid. These E. coli have a different shape and reproduce slowly. The synthetic E. coli genome is four time larger (four million base pairs) and more complex than previous synthetic genomes. Chin’s research aims to probe into why the genetic code has so many redundancies, as 20 amino acids are coded for by 61 codons instead of just 20 codons. Universally, life uses 64 codons, but Chin’s group created an organism that uses 61 codons to produce all the amino acids needed. Small segments of the genome were built and swapped into the E. coli genome bit by bit until no natural segments were left. 

Eukaryotic genomes

The Synthetic Yeast Genome project (Yeast 2.0 or Sc2.0) will be the first eukaryotic genome to be synthesized, and as human are eukaryotic as well, it provides groundwork for synthetic human genome projects. Genome writing in yeast could also lead to new uses for yeast, such as production of biofuel or other useful compounds. Sc2.0 is one of the main initiatives of the Genome Project-write. The main portion of the details of the construction of five out of 16 chromosomes that make up the yeast (Saccharomyces cerevisiae) genome, lead by Jef Boeke and his Sc2.0 team was published in Science in 2017. To build their first chromosome, which is the shortest, took nearly 10 years. It took less than three years to generate the next five chromosomes, which includes the longest one. 



The production of an ultra-safe human cell line for cell therapies for production of therapeutic proteins is a Genome Project-write pilot project. Synthetic versions of human genomes are planned to be recoded, the three letter DNA sequences called codons changed, to make cell lines resistant to viruses, radiation, freezing, aging or cancer. It is possible to change or rewrite the genetic code to eliminate susceptibility to viruses without changing the amino acid sequence of the protein because of redundancy. Multiple codons that code for the same amino can be swapped. 

Viral genomes

In 2002, poliovirus was synthesized as a cDNA sequence by Eckard Wimmer’s research group at State University of New York at Stony Brook. It was the first synthesis of a replicating ‘organism’ in the absence of a natural template. ‘Organism’ is in quotes because viruses do not meet all criteria to be considered a living organism. Poliovirus is an RNA virus and the corresponding cDNA sequence of the virus was synthesized by nucleotide assembly. The synthetic poliovirus cDNA was transcribed into viral RNA by RNA polymerase and translated and replicated in cell-free extract, resulting in infectious poliovirus. The experiment demonstrated that it was possible to synthesize an infectious agent chemical-biochemical means. The production of infectious poliovirus in a cell-free extract lacking nuclei and DNA demonstrated that viruses do not need cell proliferation nor a functional genome in the host in order to replicate and produce viral particles. The synthetic poliovirus publication also showed that viruses cannot be declared extinct as long as their genome sequence is known, since they can be resurrected in vitro. 



The publication of the synthetic poliovirus sequence received criticism for being irresponsible due to the threat of bioterrorism. In January 2003, the US National Academy of Sciences and the US-based Center for the Strategic and International Studies in Washinton, DC, met to discuss pressing issues around bioterrorism, as a group which included journal editors, authors, members of government, secret service personnel and journalists. Guidelines for journal editors and authors were created to guard against dissemination of potentially dangerous information. The workshop considered that the purposes of the poliovirus synthesis to establish a proof of principle and to sound a wake-up call, as reasonable. 



In 2003, the de novo synthesis of the bacteriophage φX174 genome was published by J. Craig Venture and his team. The synthetic phage DNA was transfected into bacteria and produced viable phage viruses. In 2005 the Spanish influenza virus was resurrected for the purpose of understanding the molecular mechanisms by which is caused the influenza pandemic of 1918-1919 for the purpose of helping to prevent future outbreaks from similar virus strains. 



Timeline

May 15, 2019

Total synthesis of Escherichia coli with a recoded genome

Nature 569, 514–518 (2019)

March 10, 2017

Design of a synthetic yeast genome

Science 10 Mar 2017:

Vol. 355, Issue 6329, pp. 1040-1044

DOI: 10.1126/science.aaf4557

July 2, 2010

Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome

Science 02 Jul 2010:

Vol. 329, Issue 5987, pp. 52-56

DOI: 10.1126/science.1190719

October 7, 2005

Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus

Science 07 Oct 2005:

Vol. 310, Issue 5745, pp. 77-80

DOI: 10.1126/science.1119392

November 3, 2003

Generating a synthetic genome by whole genome assembly: φX174 bacteriophage from synthetic oligonucleotides

PNAS December 23, 2003 100 (26) 15440-15445; https://doi.org/10.1073/pnas.2237126100

August 9, 2002

Chemical Synthesis of Poliovirus cDNA: Generation of Infectious Virus in the Absence of Natural Template

Science 09 Aug 2002:

Vol. 297, Issue 5583, pp. 1016-1018

DOI: 10.1126/science.1072266

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Reconstruction of the 1918 Influenza Pandemic Virus | CDC



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The test-tube synthesis of a chemical called poliovirus: The simple synthesis of a virus has far-reaching societal implications



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With 'recoded' synthetic genome, scientists give life new dictionary - STAT



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May 15, 2019

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