Revolutionary Advances in Genomic Engineering

The area of study encompassed by genomic engineering has made so many technological advances that the modification of genomes – including the human genome – has rapidly come within the reach of those adequately trained in the techniques and methodologies of molecular biology.

There have been two extraordinary technological advances in the field of molecular biology that have made the ability to modify specific genes a reality.  First of all, the complete sequencing of the human genome in 2003 has made it possible to identify the genes implicated in many cellular and disease processes.  Secondly, the use of cluster regularly interspaced short palindromic repeats (CRISPRs) together with Cas9 has made it possible to specifically engineer the modification of literally any targeted gene.   Cas genes code for proteins that are directly related to CRISPR activity.

The CRISPR-Cas9 system was discovered in prokaryotic cells, bacteria for example.  It has been shown that this system provides protection from foreign genetic elements such as plasmids and phages- phages are viruses that target prokaryotic cells - that often attack prokaryotic cells.  This system has been likened to acquired immunity found in more complex organisms such as human.

CRISPRs are found in approximately 40% of sequenced bacteria genomes.  CRISPRs are, in fact, composed of segments of prokaryotic DNA made up of short repetitions of base sequences followed by segments of so-called, "spacer DNA."   These spacer segments seem to result from the cell’s previous exposure to an invading organism and serve as a template for the production of RNA transcription products that interact with Cas gene – related proteins in a system designed to inactivate invading phages or plasmids.

Since 2013, the CRISPR-Cas9 system has been adapted for use in the specific editing of genes.  When a specifically engineered CRISPR-Cas9 system is introduced into a host mammalian cell such as human it can alter a target gene in a very specific way.  This was amply demonstrated when researches at MIT effectively used this approach to effectively cure mice of a rare genetic liver disorder.   

This is such a powerful technique carrying with it such profound implications for the future of genetic engineering that in January of 2015 a group of those scientists intimately associated with these studies met in Napa, California at the Innovative Genomics Initiative (IGI) Forum on Bioethics to discuss the scientific, medical, legal and ethical implications of their work.

A Possible New Treatment Option for Patients with Acute Myeloid Leukemia (AML)

AML is the most common form of adult leukemia accounting for some twenty-five percent of adult patients with leukemia.  The standard protocol for treatment involves a shot-gun approach using non- selective chemotherapy to induce successful remission.   Although this clinical methodology has shown to be effective for most patients, other avenues of treatment are needed for those who prove refractory to the standard approach and to those patients who cannot endure high dose chemotherapy.

The biology of cancer cells has progressed dramatically since the complete sequencing of the human genome.  As a result, it has been clearly established that cancer is the result of genetic mutations that involve either/or those genes referred to as proto-oncogenes involved in normal cell division and tumor suppressor genes involved in the normal suppression of cell division The new era of cancer treatment involves the development of methodologies to specifically target these mutations either by developing specialized drugs to target these changes or mobilizing the immune system through targeted immunotherapy.

Dr. Anuradha Illendula and his colleagues from the Department of Molecular Physiology and Biological Physics at the University of Virginia in Charlottesville, using the mouse animal model,  have developed a small molecule referred to as AI-10-49 that effectively binds to a transcription factor subunit referred to as core bind factor β (CBFβ).

Molecular Structure of AI-10-49 -

  

   

These investigators were able to show that the use of A!-10-49 not only prolonged the survival of mice transplanted with leukemic cells without any observable toxic effects but was also able to inhibit the proliferation of a sub-type of human AML cells grown in culture.  These findings are of particular importance for this approach may serves as a model for development of drugs specifically targeting "uninhibited cell division resulting from genetically altered transcription factor function."