The Nobel Prize in Chemistry in 2020 for CRISPR, a Technique of Genome Editing
In October 2020, the Nobel Prize in Chemistry was announced as shared by Jennifer Douda at the University of California, Berkeley and Emmanuelle Charpentier of the Max Planck Unit in Berlin for their technique of genome (gene) editing, called CRISPR* (pronounced “crisper”). The prizes are announced in October, the month of Alfred Nobel’s birth and awarded, under normal circumstances, in Stockholm, on December 10th, the date of Alfred Nobel’s death. The scientists selected were chosen because of the procedure’s potential to enhance our understanding of molecular biology and genetics, to develop therapy for genetic disorders, to advance innovative drug development, to improve agricultural productivity and more. The technique is being actively explored for the treatment of human genetic diseases and has been successful in a small number of cases of inherited blood cell disorders so treated. The procedure may be so impactful, we should be familiar with its general outlines.
Sometimes, it is difficult to decide which of the Nobel Prizes for science should be awarded for physics, chemistry or, instead, physiology or medicine. The decision is related to timing in that when first awarded it is not always clear that medicine will derive great benefits from the discovery. Wilhelm Konrad Röentgen won the Nobel Prize in Physics in 1901, the first year of the awards. The Prize was given for the discovery of a heretofore undescribed electromagnetic emissions at a wavelength, he called X-ray, using X for an unknown quantity. Their potential in medicine was not immediately evident to the Nobel review committee, but was highlighted by the first X-ray, an image of his wife’s hand showing its skeletal structure, an outline of the surrounding soft tissues and an image of her wedding band. X-rays were eponymously referred to as Röentgen rays and the technique, Röentgenography, proved to be an incalculable advance in diagnostic and therapeutic medicine.
A Primer on Genetics
It is estimated that there are 10,000 inherited human single gene disorders. This estimate is not surprising in that there are approximately 19,000 protein-encoding genes in the human genome. Remarkably, they are able to direct the synthesis of hundreds of thousands of proteins by a process known as “alternative splicing” in which one gene can result in the formation of many messenger RNA molecules. The latter contain the message to form a protein product. DNA “transcription” results in messenger RNA and messenger RNA “translation” results in a protein. Messenger RNA directs the specific protein to be synthesized. Thus, by generating multiple different types of messenger RNA per gene (stretch of DNA) the number of proteins formed per gene is multiplied many times. Although much is known of the genome, many mysteries remain.
Examples of genetic disorders caused by the mutation of a single gene include hemophilia A, hemophilia B, sickle cell disease, cystic fibrosis, Huntington disease, muscular dystrophy and many other rarer diseases. These monogenic disorders are referred to as Mendelian genetic disorders because they follow the inheritance patterns described by the Augustinian friar Gregor Mendel in his studies of the inheritance of phenotypic characteristics in generations of pea plants in his monastery garden in the mid-1800s. His treatise was one of the two most impactful discoveries in biology along with the nature of speciation proposed by Charles Darwin in his monumental treatise On the Origin of Species by Means of Natural Selection, both published in the mid-19th century.
The Application of CRISPR
CRISPR is a method of gene editing by which one can silence a disease-causing mutant gene or replace an undesirable gene with a different one. The latter process, gene insertion, is far more difficult that gene deletion. Using CRISPR scientists can edit parts of the genome of a cell by excising, inserting, or modifying sections of a DNA base sequence (a gene), giving it the potential to correct inherited errors of the genome. In effect, one engineers a guide RNA that can locate its precise complementary stretch of DNA, the gene in question. Thanks to the human genome project we know the sequence of DNA bases that represents our protein encoding genes. Attached to the guide RNA is a molecular scissors, an enzyme, designated by the acronym Cas*, that can cut the section of DNA one wants to remove; then the DNA reanneals, using its inherent repair mechanism. The technique is being used to explore the behavior of cells after manipulation of their genome, to alter stem cells that can be used to correct errors in the descendants of those cells, and to figure out safe means to correct innumerable inherited disorders.
The application of CRISPR is used to edit the genome of somatic (not reproductive) cells. Gene editing in human reproductive (germ) cells such as a sperm, egg, or an early embryo is prohibited in many countries and is appropriately controversial. Moreover, potentially introducing errors in germ cells is profoundly consequential. It is very early in this story, but the potential is great for medical therapy, new pharmaceuticals and agricultural productivity, hence the recognition by the Nobel Foundation and the importance of an informed citizenry knowing that CRISPR is not a request to toast rye bread twice.
*CRISPR is an acronym that represents the initials of the phrase “Clustered Regularly Interspaced Short Palindromic Repeats” originally discovered in bacteria, where it is part of an immune mechanism to protect bacteria against invasive viruses. Cas is the acronym for CRISPR-Associated Protein (enzyme)
Written November, 2020