The CRISPR Phenomenon

" The science of today is the technology of tomorrow"  - Edward Teller

Scientific progress is the end result of current and past research. Only a few scientific discoveries in history have singularly influenced humanity, such as those whose discovery ignited further rapid successions of discoveries. The development of the atom bomb is one such example, in which 12 years of scientific research brought a concept held by Dr. Leo Szilard (1933) to realization and the devastation of two Japanese cities. The CRISPR phenomenon is another discovery associated with rapid technological progression and which inspires many scientists world wide.

Jennifer Doudna/UC Berkeley. Used with permission. Original.

The CRISPR discovery and following research aims at improving human life. CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats, are repetitive elements which are interspaced by non-repetitive elements commonly called "spacers". Recent research concerning this biological phenomenon has taken a different and exciting path toward the next generation genome manipulation and genetic therapy such that some scientists see it as a double edge blade that will eventually turn against humanity in the future.

Standing on the shoulders of giants, the path from the initial discovery to the "The CRISPR craze", as Science magazine titled recent events, is a remarkable example how discoveries pieced together can quite quickly reach an unprecedented technological advancement.

From unusual sequences to human gene therapy

The first public note related to CRISPR was published by a small Japanese team (Ishino 1987), that commented at the end of the paper's discussion that "An unusual structure was found in the 3'-end flanking region of iap… So far, no sequence homologous to these has been found elsewhere in procaryotes, and the biological significance of these sequences is not known." Fifteen years later a bioinformatics research group identified this pattern to be common among other bacterial strains as well as within Archaea genome, coining the term CRISPR and highlighting several associated genes termed Cas which "may be suggestive of a role for the Cas proteins in the genesis of CRISPR loci." (Jansen 2002). Soon, a French group was the first to publish their  discovery that Yersinia pestis bacteria have been preferably acquiring bactriophage DNA into the CRISPR spacers (Pourcel 2005) and suggested an explanation "that  CRISPRs  are  structures  able  to  take  up  pieces  of foreign DNA as part of a defence mechanism…may represent a memory of past ‘genetic aggressions’". Right on their heels, three additional independent groups have published their results further providing strong support how foreign DNA is incorporated into the CRISPR. Two years later, research led by Danisco researchers (DuPont) provided the first experimental evidence that indeed CRISPR and the associated Cas proteins act as a bacterial anti-viral mechanism (Barrangou 2007). This publication led to explosion of research (over 400 articles in less than five years!) focused on multitude angles of the CRISPR phenomenon as well as deciphering part its mechanism. Currently, three CRISPR systems are known (Type I-III) which differ in their gene conservation and locus organization. The first phase of the CRISPR mechanism is the incorporation of foreign DNA (phage or plasmids) into the CRISPR locus while maintaining the same flanking repetitive repeats. The next step is the transcription and processing of the CRISPR locus into short (60bp) RNA segments termed crRNAs.  The collection of crRNAs fragments bind to Cas proteins and act as ribonucleoprotein complexes, enabling the base pairing of the crRNA to any foreign target DNA which is subsequently digested by the ribonuclease catalytic activity of the Cas protein, thus eliminating secondary infection by the same phages or plasmids. However, the twist in the CRISPR story took place when two groups published back-to-back studies demonstrating that the type II CRISPR can be utilized for genome manipulation in human and mouse cells (Cong 2013, Mali 2013), opening the door for a quick-pace barrage of studies demonstrating the robustness of this method in Arabidopsis, zebrafish, drosophila, human stem cells and more.  

CRISPR – what's next?

Since CRISPR enables a surgical and relatively easy manipulation of the host genome, and in light of the success of several research groups to manipulate selected animal models and plants, it is clear that genome editing will push forward the evaluation of gene's responsibility at the whole organism level. Cell line's genome can be as easily manipulated (as well as stem cells) and thus the next thing is human gene therapy and in-vitro fertilization (IVF) manipulations are already on the horizon. These two aims are the most promising yet the most feared from. While the potential to eliminate certain diseases at the embryo level, what will stop science and progression from using CRISPR to optimize the next generation (super) human being? This might indeed sound like science fiction, yet similar global debate took over the world when the news of the cloning of Dolly broke out on the eve of March 1997. The New York Times recently took a retrospect visit to that sensational story of science at that decade, and realized how embryonic stem cell push forward science yet as it stands for clinical therapies these are still far from the fears and promises that shook the world at that time. In light of Dolly's story, will this scenario repeats itself for CRISPR? Can the challenges of gene therapy in humans (with strict regulation by the FDA) be overcome? Clearly, it is only a matter of time till the first biomedical startup will jump into the icy cold waters of pre-clinical and clinical arena and boldly test the clinical application of CRISPR. We'll wait and see.

What do you think? Will CRISPR be another great scientific technique or the next generation of gene therapy?

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