Highlights in this article:

Dr. Church’s research group demonstrated the feasibility of establishing a genetic firewall in organisms through the discovery of viral tRNAs that facilitate efficient codon reassignment. The amino acid-swapped genetic code resulting from this approach confers resistance to viral infections and prevents the leakage of synthetic genetic information. These findings hold great potential for developing a general strategy to safely shield any organism from natural viruses while preventing the flow of genetic information into or out of genetically modified organisms.

Background:

Viruses are small infectious agents that invade living cells and replicate themselves by hijacking the host cell’s machinery. They can infect all types of organisms, including humans, animals, plants, and bacteria. Virus infection in bacteria, also known as bacteriophage infection, is a well-studied phenomenon that has contributed significantly to our understanding of molecular biology. One of the ways in which viruses can infect bacteria is by transferring their genetic material into the host cell. This transfer of genetic information is facilitated by mobile genetic elements such as plasmids, transposons, and integrons. However, some viruses and mobile genetic elements can also encode parts of the translational apparatus, including transfer RNA (tRNA).

tRNAs are small RNA molecules that play a crucial role in protein synthesis by carrying amino acids to the ribosome, where they are added to the growing peptide chain. There are 20 different amino acids used to build proteins, each of which is carried by one or more specific tRNAs. The genetic code is degenerate, meaning that multiple codons can code for the same amino acid. For example, there are six different codons that code for serine, a non-essential amino acid.

Discovery:

Dr. Church’s research group has shown that mobile tRNAs can enable gene transfer and allow viral replication in Escherichia coli, a common model organism for molecular biology research. They found that the removal of three of the 64 codons and their corresponding tRNA and release factor genes did not prevent viral replication. However, they were able to establish a genetic firewall by discovering viral tRNAs that provided efficient codon reassignment. By developing cells with an amino acid-swapped genetic code that reassigned two of the six serine codons to leucine during translation, they rendered the cells resistant to viral infections. This is because the viral proteomes would be mistranslated due to the different amino acid sequence resulting from the codon reassignment. This also prevents the escape of synthetic genetic information by engineering reliance on serine codons to produce leucine-requiring proteins.

Furthermore, as these virus-resistant cells may have a selective advantage over wild organisms, the researchers also repurposed a third codon to biocontain this virus-resistant host by depending on an amino acid not found in nature. This prevents the spread of the virus-resistant genetic code to other organisms in the environment.

This study provides a significant contribution to our understanding of virus infection and gene transfer. It highlights the importance of developing strategies to prevent viral infections and genetic information flow into and out of genetically modified organisms. The discovery of efficient codon reassignment through viral tRNAs offers a promising approach to develop a general strategy to make any organism safely resistant to all natural viruses.

For more information:

Nature 2023 3/15

https://www.nature.com/articles/s41586-023-05824-z

A swapped genetic code prevents viral infections and gene transfer

Dr. Church’s website:

https://genetics.hms.harvard.edu/faculty-staff/george-church

Dr. George M. Church is a renowned American geneticist and molecular engineer who has made significant contributions to the field of genetics and genomics. He is widely known for his groundbreaking work on DNA sequencing and synthetic biology, which has paved the way for many advancements in biotechnology and medicine. Dr. Church’s achievements in the field of genetics are numerous and far-reaching. He is credited with co-developing the first direct genomic sequencing method in 1984, which revolutionized the way genetic information is collected and analyzed. He also played a key role in the Human Genome Project, an international effort to map the entire human genome, and was one of the first scientists to sequence his own genome. In addition to his work on DNA sequencing, Dr. Church has made significant contributions to the field of synthetic biology. He has developed methods for synthesizing DNA and RNA, and has engineered new organisms with novel functions. This work has the potential to lead to the development of new drugs, fuels, and materials. Dr. Church has also been a pioneer in the field of genome editing. He co-founded Editas Medicine, a company that is developing gene editing therapies for a range of genetic diseases. He has also been involved in the development of CRISPR-Cas9, a powerful genome editing tool that has revolutionized the field of genetics. Throughout his career, Dr. Church has received numerous awards and honors for his contributions to genetics and biotechnology. He is a member of the National Academy of Sciences and the National Academy of Engineering and has been recognized as one of Time magazine’s 100 most influential people in the world. His work has the potential to shape the future of medicine and biotechnology, and his contributions to the field of genetics will be remembered for generations to come.