The 2019 Lectures in Biology and Chemistry: Genome Editing

The complete set of base sequences of the DNA of an organism, called “the genome”, contains all of the necessary information and the instructions for building the different cell types and maintaining the functions of the organism. Alterations (mutations) in the genome sequence may have profound phenotypic consequences, depending on their location. Mutations in protein-coding regions of a gene may lead to altered protein function, while changes in the non-coding part of the genome may influence the regulation of the expression of genes.

Genome Editing, a type of genome engineering, refers to strategies and techniques, which allow the correction of specific mutations within the genome for therapy applications or the introduction of changes for research purposes. Since the late 1980s, homologous recombination (HR) in Embryonic Stem cells (ES cells) was the sole and most widely used approach for engineering genomes to study gene function in different experimental model organisms. Due to the requirement for the generation of complex targeting constructs and the very low targeting efficiency, genome engineering by this approach was lengthy, expensive and a highly elaborate task. More importantly, given the low efficiency of targeting, classical HR approaches were impractical for engineering somatic cells. However, in recent years, new highly versatile tools have been developed, which made it possible to change the DNA sequence of living organisms with unprecedented ease and precision.

The discovery of restriction endonucleases by the group of Hamilton Smith offered, for the first time, the technical potential to perform a non-random “operation” on the double helix at the level of base-pair resolution. Another contemporary discovery was that of Zinc Finger family of transcription factors, the first structure of which was determined by Jeremy Berg, only a few doors down from where restriction endonucleases were discovered. The interaction between these two groups was extensive and seeded some novel ideas for future application in the mind of a beginning investigator who proposed to combine the base sequence-recognition of Zinc Finger factors with some non-specific endonucleolytic activity. In doing so they create a molecular chimera which could be directed to make incisions on the double helix with base-pair specificity at a preselected site. “Chance favors the prepared mind” had said, Pasteur several years earlier! That idea, materialized by Dr. Chandrasegaran, yielded the first ZFN and opened the way to targeted genome editing, albeit with high costs and extensive efforts. But, that paradigm was followed by rapid discoveries. and by today we have the choice of faster and more diverse ways of performing genome surgeries.

The three major types of technologies, in order of chronological discoveries, are the so-called , Zinc Finger Nucleases (ZFNs), the Transcription Activator-Like Effector nucleases (TALENs) and the CRISPR/Cas9 system. All such “tools” share a common organization motif: a sequence-recognition domain that guides the tool to the desired target and an effector domain that cuts the DNA sequence exactly at the desired site, and thus allowing the “genome surgery” to be performed.

The Zinc Finger Technology utilizes engineered zinc finger DNA binding domains, derived from transcription factors (for the specificity), which are fused to the FokI nuclease domain to execute the cutting operation. Specific zinc fingers designed to recognize different nucleotide triplets, activate the endonuclease via dimerization, which in turn introduces a double stranded break between the two distinct zinc finger binding sites, and stimulates site-specific recombination and modification of the genome.

TALENs represent a technical variation/evolution of ZFNs. TALENs consist of a fusion of TALEs, derived from the Xanthomonas bacteria, again fused to the nuclease domain of FokI. By modifying the amino acid repeats in the TALEs, one can customize the system to specifically bind target DNA and induce cleavage by the nuclease between the two distinct TAL array binding sites.

The CRISPR/Cas system does not depend on a specific protein construct to home-in to the desired gene site. Instead, it depends on a short guide RNA (gRNA) to recognize target DNA regions that activate endonuclease motifs to induce the site-specific cleavage. These constructs are derived from the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) found in bacteria that serve to identify and destroy foreign DNA, acting as a type of bacterial “immunity”. The CRISPR methodology is characterized by its relative simplicity and lower cost requirement to yield the desired result and for this it has become one of the most widely-used method today.

The above systems, each with different cost and effort requirement, have revolutionized almost every field of biology. During the short time since their discoveries, gene editing tools have been used in numerous applications, including the introduction of mutations that will model human disease, the building of complex synthetic signaling networks to perform regulated functions, genetic mutation detection or design and generate cells to study and cure specific disease states.

This year’s Onassis Lectures are dedicated to the ground-breaking gene editing technologies. The lead speaker is Jennifer Doudna a co-inventor (with Emmanuelle Charpentier) of the CRISPR, who turned an ancient mechanism of bacterial immunity into a powerful and general technology with wide-ranging applications in biological research and/or clinical practice. The individual presentations will cover a wide range of topics related to the development and applications of different gene editing approaches.

Jennifer Doudna
Professor, UC Berkeley,

Dana Carroll
Professor, University of Utah, USA

Srinivasan Chandrasegaran
Professor, Johns Hopkins University, USA

Andrea Crisanti
Professor, Imperial College London, UK

Zoe Hilioti
Senior Investigator, Center for Research and Technology, CERTH, Greece

Maria Jasin
Senior Investigator, Sloan Kettering Institute, USA

Eva Nogales
Professor, UC Berkeley, USA

Erik Sontheimer
Professor, The University of Massachusetts Medical School, USA

NEW Deadline for Application
Friday June 7, 2019



Researchers, Postdoctoral Associates, Graduate
and advanced Undergraduate students.

Financial Aid


The Onassis Foundation will support travel and accommodation expenses for up to thirty five Greek students and up to fifteen International students, selected on the basis of their academic performance. The financial aid for the travel of non-European students cannot exceed the maximum amount of the reimbursement provided for the travel of European students. Interested students should attach to their CV, a list of courses taken, their grades and two letters of recommendation. Excellent knowledge of English is required.



Students admitted on the basis of their academic performance will receive a certificate after successful participation in the lectures.


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