Top 25 Most Recent Genetic Discoveries in 2018

Specific nucleases such as Cas9 and recently discovered Cas12 are already revolutionizing research and therapy.

• The discovery of new nucleases, Cas13a and CAs13b, have made single-strand RNA editing possible as well.
• Plant biologist view this new tool as an exciting gift. First, RNA editing allows post-transcriptional modification of gene expression. Second, it is a powerful tool for combating RNA-based viruses infecting plants.
• There are potential other applications for this new technology, and combining DNA and RNA editing can allow complex manipulations of metabolism in plants.

Reference: Wolter, F., H. Puchta. (25 March 2018) The CRISPR/Cas revolution reaches the RNA world: Cas13, a new Swiss Army knife for plant biologists. The Plant Journal, June 2018, V. 94, Issue 5, pp. 767-775. Link.

One of the reasons that cancer is so hard to treat is that its cells mutate frequently.

• Because of this, there are multiple clusters of genetically different cells in a tumor. M.Anjanappa et al. have developed a system that involves isolating and cultivating tumor cells.
• This system allows scientists to identify previously undetected mutations in various subsets of the tumor cell population.
• This approach can help understand the composition of cancer tumors better and develop new treatment strategies.

Reference: Anjanappa, M. et al. (11 September 2017). A system for detecting high impact-low frequency mutations in primary tumors and metastases. Oncogene, January 2018, V. 37, pp. 185–196. Link.

Recently, non-coding RNAs (ncRNAs) have become a focus of extensive research.

• Those molecules participate in modulating transcription and epigenetic regulation of genome activity.
• Among other things, some ncRNAs were proposed as biomarkers of disease progression in cancer.
• They can be easily detected in biological liquids, such as blood or urine, and used for evaluation of the patient’s condition.
• However, the sheer number of these molecules and lack of consistent analysis points to the necessity of strict rules in the detection of such molecules.

Reference: De Bortoli, M., L. Miano, L. C. Tarrero. (April 23, 2018). The new world of RNA biomarkers and explorers’ prudence rules. The international journal of biological markers, 2018, V. 33. Issue 3. Link.

DNA methylation is a crucial epigenetic mechanism that regulates gene activity.

• Small RNAs (sRNAs) are a typical example of the tools that promote such epigenetic control. sRNAs can direct methylation at specific sites of the genome and can travel from cell to cell in the plants, thus controlling their development.
• At present, the study of sRNAs is a booming research field that allows plant specialists to understand the genome activity in plants better.

Reference: Tamiru, M., T. J Hardcastle, M. G. Lewsley (06 November 2017). Regulation of genome‐wide DNA methylation by mobile small RNAs. New Phytologist Trust, January 2018, V. 217, Issue 2, pp. 540-546. Link.

DNA is often referred to as a “molecule of life“.

• DNA is now the original recipe for protein synthesis, but there is also RNA that has multiple functions, including regulatory activity.
• More pieces of evidence suggest that this versatile molecule was the first “molecule of life” on Earth.
• Moreover, the first RNAs were produced without the assistance of proteins. In 2018, Zhang et al. have used a series of crystallography-based “images” to document the step-by-step the process of synthesis of RNA without enzymes – proving that such process was indeed possible in the past.

Reference: Chaput, J. C. (May 31, 2018) RNA World: Visualizing primer extension without enzymes. eLife 2018;7:e37926. Link.

A novel, precise method of gene editing in mature neurons was proposed by Nishiyama et al.

• His method used three components: homology-based DNA repair machinery containing Cas9, a guide RNA for specific sequences, and an adeno-associated virus.
• Using this system, Nishiyama’s team has managed to edit sequences both in embryonic neurons and in adult neurons in aged mice, which opens many possibilities for treatment of nervous disorders, including epilepsy.

Reference: Richner, T. J., E. Krook-Magnusson (March 1, 2018). Progress toward Precise Genetic Repair in Neurons. Epilepsy Currents, 2018, V. 18, Issue 2, p. p.121-122 Link.

Genetically modified objects, or GMOs, are not a novel concept.

• Despite being viewed with suspicion, they are the answer to maintaining important crops prone to diseases and other threats.
• With undernourishment and malnutrition being huge issues in various areas of the world, the need for safe and resistant crops is undeniable.
• Improvements in modern gene editing technologies make such plant genome editing much more precise and safer.
• It allows the new crops to become more resistant to diseases, as well as counteract the deficit of specific micro-and macronutrients in the diet.

Reference: Ma, X., Mau M., Sharbel T. F. (February 2018). Genome Editing for Global Food Security. Trends in Biotechnology, 2018, V. 36, Issue 2, pp. 123-127. Link.

Bcl-2 and related proteins play a crucial role in inducing cell death and cellular differentiation.

• This protein is also a key component in the development of some cancers, especially certain types of lymphomas and leukemias.
• The extensive research devoted to this class of proteins has led to the development of a specific Bcl-2 inhibitor – venetoclax.
• This agent can help patients with certain types of chronic lymphocytic leukemia.
• The drug development would certainly not stop there – other members of this family are also potential drug targets which significantly help in cancer treatment.

Reference: Reed, J. C. (11 December 2017) Bcl-2 on the brink of breakthroughs in cancer treatment. Cell Death and Differentiation, 2018, V. 25, pp. 3–6. Link.

CRISPR-Cas9 machinery has developed in bacteria as a defense mechanism against viruses.

• Having discovered these systems, the scientists now turn the bacterial machinery against the creators themselves.
• As scientists find more new proteins in this family, they also develop novel protocols that allow effective manipulation of metabolism in bacterial cells.
• Previously, mainly E. coli was the beloved model of such engineering. Now, with novel systems, the scientists can turn more bacterial species into cell factories, including Clostridia spp., Bacilli spp., Streptomycetes spp., and even Cyanobacteria.
• As each type of bacterial cell can produce its own substances, endless possibilities are opening up in biotech.

Reference: Mougiakos, I. et al. (April 2018). Hijacking CRISPR-Cas for high-throughput bacterial metabolic engineering: advances and prospects. Current Opinion in Biotechnology, 2018, V. 50, pp. 146-157. Link.

Gene editing in mice is a convenient tool for studying the role of specific genes in mutations in health and disease.

• Until recently, this process involved multiple steps including oocyte microinjections.
• Texeira et al., proposed a much more simplified and direct approach using ribonucleotide complexes containing Cas9 and guide RNA.
• This approach avoids unnecessary damage to the cell and allows the generation of deletions in target genes in mouse zygotes.

Reference: Teixeira, M. et al. (11 January 2018). Electroporation of mice zygotes with dual guide RNA/Cas9 complexes for simple and efficient cloning-free genome editing. Scientific Reports, 2018, V. 8, Article number: 474. Link.

Staphylococcus aureus is a common bacterial agent that becomes resistant to multiple antibiotics and even bacteriophages.

• As common treatments are becoming ineffective, G.Ram and his colleagues propose a novel method. Their team has engineered a common bacterial structure – pathogenicity islands.
• The editing has turned them from toxin-producing factories into so-called antibacterial drones. Once the drone-carrying bacteria are introduced into the bacterial population, the drones destroy the intact bacterial cells.
• The efficacy of the approach was proven in mice. Mice injected with bacteria that contain bactericidal drones survived a lethal S. aureus infection.

Reference: Ram, G. et al. (24 September 2018). Conversion of staphylococcal pathogenicity islands to CRISPR-carrying antibacterial agents that cure infections in mice. Nature Biotechnology, 2018, V. 36, pp. 971–976. Link.

Each species has its own chromosome number, and unbalanced changes to this species-specific number can lead to disorders.

• Chromosome fusion, on the other hand, is not so disastrous. The team of scientists has taken yeast cells that typically contain 16 chromosomes and created lines that contained 8, 4 or 2 fused chromosomes instead, using CRISPR.
• It was found that the organisms with fused chromosomes could function normally, but yeast cells with different chromosome numbers could not produce viable spores.
• This experiment has shown that chromosome fusion can also become a reason for the reproductive isolation of the population and new species development.

Reference: Luo, J. et al. (1 August 2018) Karyotype engineering by chromosome fusion leads to reproductive isolation in yeast. Nature, 2018, V. 550, pp. 392–396. Link.

With the use of genome editing toolkit, Y.Shao and colleagues have managed to merge 16 chromosomes of the yeast Saccharomyces cerevisiae into a single chromosome.

• Though the overall chromosome structure was considerably changed, the yeast cells with such chromosomes could maintain regular activity, but could not survive in certain environments.
• This experiment offers a novel way to study the evolution of eukaryotic genomes.

Reference: Shao, Y. et al. (August 1, 2018). Creating a functional single-chromosome yeast. Nature, 2018, V. 560, pp. 331–335. Link.

The last several years were undoubtedly the CRISPR-CAS9 period. This system, used by bacteria and archaea as protection against viruses, is now the most advanced tool for gene editing since the 1970s.

• The scientist race to produce more effective, smaller and specific editing systems. With the increased specificity and flexibility, novel applications of the system regularly appear.
• Besides inducing mutations and introducing new sequences, this toolkit is now used for:
• introducing novel stop codons;
• manipulating gene expression;
• visualizing chromatin changes;
• modulating the epigenetic changes to the genome;
• screening multiple genes at the same time, using some guide RNAs.

Though enormous progress has been made in this field, developing appropriate and safe vectors for delivery of the systems remains a problem. It is quite likely that the next few years would probably be devoted to their development and improvement.

Reference: Adli, M. (May 15, 2018). The CRISPR tool kit for genome editing and beyond. Nature Communications, 2018, V. 9, Article number: 1911. Link.

Hepatitis B and C viruses can cause cirrhosis and hepatocellular carcinoma.

• One of the mechanisms that help them resist available treatment is the formation of cccDNA during viral replication.
• The discovery of CRISPR/Cas9 systems has provided the researchers with a tool that can destroy it. For instance, a CRISPR/Cas9 system isolated from Francisella novicida was able to destroy the HCV virus, including its cccDNA form, in the culture of HCV-infected cells.
• The approach can’t be translated to human treatment, as it is not yet clear how the editing proteins are to be delivered into the infected cells.

Reference: Moyo, B. (January 15, 2018). Advances with using CRISPR/Cas-mediated gene editing to treat infections with hepatitis B virus and hepatitis C virus. Virus research, 2018, V. 244, pp. 311-320. Link.

Spinal muscular atrophy is a disease of the motor caused by a mutation in the SMN1 gene that produces a protein crucial for normal activity of motor neurons.

• With genetic mechanism known, it has become possible to control the SMN protein production.
• One of the most promising treatment strategies involves using neuron-specific adeno-associated vector, AAV9 that carries the correct SMN1 gene and can replace the mutated gene in the motor neurons.
• The vector was already tested in mice and brought considerable improvement. As the experiments were successful, clinical trials in infants with SMA are currently being initiated.

Reference: Sumner, C. J., T. O. Crawford. (July 9, 2018). Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain. The Journal of clinical investigation, 2018, V. 128, № 8, pp. 3219-3227. Link.

Rett syndrome is a genetic disorder of the brain associated with mutations in the X-linked MECP2 gene.

• The patients usually have smaller brain size and a variety of other symptoms depending on the level of X-chromosome inactivation.
• The treatment of this syndrome is complicated. Due to the progress in gene editing technologies, there are two potentially successful strategies – targeted inactivation of the X-chromosome carrying the mutated gene, and targeted editing of the mutated gene using the CRISPR/Cas system.
• Both treatments are expected to be most effective in infants and younger children, as the mutation influences the size of the brain.

Reference: Clarke, A.J.,A.P.A.Sheikh. (April 2, 2018). A perspective on “cure” for Rett syndrome. Orphanet Journal of Rare Diseases, 2018, V.13, P.44. Link.