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The Long Story Short - CRISPR-Cas9: Editing away sickness
Gene Editing Tool That Could Fix Disease and Eradicate Cancer
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The discovery of a gene editing tool called CRISPR-Cas9 is perhaps the most exciting finding in molecular biology since the discovery of DNA. Scientists first unearthed the structure of DNA in the 1950s, and by 2003 scientists had sequenced the entire human genome encoding for 20,000 distinct proteins. Following its discovery in bacterial immune systems, CRISPR-Cas9 was first used to replace a piece of DNA in human cells in 2013. But it was only just last year that the CRISPR-Cas9 technology advanced into human trials to treat patients with various inherited diseases and cancers. With this newfound power to edit our own genes, we could be on the verge of a medical revolution.
Many human diseases are genetically driven often caused by the mutation, deletion, or overexpression of genes. Therefore, introducing desired changes into genes has been a long sought-after goal in molecular biology. Gene editing (also known as genome editing) involves the insertion, deletion, or replacement of those chemical base pairs in DNA. DNA (deoxyribonucleic acid), the building block of genes, is used to synthesize proteins via RNA (ribonucleic acid). Genomes of eukaryotic organisms are composed of billions of DNA bases. Cas9 is an enzyme acting as a molecular “scissors” that can cut the two strands of DNA at a specific location in the genome so that bits of DNA can then be added or removed. The guide RNA (gRNA) about 20 bases long is designed to only bind to the target sequence in the DNA. The Cas9 follows the guide RNA to the same location in the DNA sequence. In order to cut a piece of DNA at the right spot, the molecular “zipper” needs to accurately match up with the piece of the DNA to form a tight bond that positions the scissors in just the right place. In CRISPR, the “zipper” is made of specially designed RNA, and the "scissor" effect comes from harnessing the natural cutting action of a protein, or enzyme, called Cas9. In this way, CRISPR-Cas9 can insert, delete, or replace the genes that have plagued humanity with
This versatile tool gives us the power to control gene expression in plants, animals, and even humans. With the ability to eradicate undesirable genes or undesirable mutations in genes, the CRISPR-Cas9 technology has the potential to revolutionize patient treatment. There are about 10,000 diseases caused by modifications in a single gene, however the application is not limited to those. The following are just a few of the diseases that the CRISPR-Cas9 technology could potentially cure.
- cancer; e.g. 30% of all cancer is driven by activating mutations of RAS gene
- blood disorders; e.g. beta-thalassemia caused by inherited mutations in HBB gene
- infectious disease; e.g. inactivating mutations to HIV virus
In addition, CRISPR-Cas9 technology has been implemented by another revolutionary treatment method called Chimeric Antigen Receptor (CAR) T cell therapy. CAR-T and CRISPR are used to harnesses the power of the human immune system in cancer treatment.In the near future, we could be able to diagnose a patient with a genetic disease, sequence their genome, and customize a genome-editing drug to treat the patient by targeting specific mutation.
With Great Power Comes Great Responsibility
In this early stage of development, CRISPR-based therapeutics faced some challenges including its delivery, safety, and pharmacology. Introducing a complex set of components into an individual organ system and delivering those components to the right organs is complicated. The off-target effect where CRISPR activity is observed in unintended parts of the genome poses risks to safety. After the first human trials were initiated, two reports in Nature Medicine emerged associating the technology with a cancer risk. Both reports focused on the classic tumor suppressor gene (p53), whose activation induces apoptosis, cell cycle arrest, or senescence in response to distinct stimuli, including DNA damage or aberrant oncogene activation. Haapaniemi et al. showed that cutting the genome with CRISPR-Cas9 induced the activation of p53. Ihry et al. emphasized the necessity to ensure functional p53 before and after gene edited cells. These findings suggest “if CRISPR worked, it was because p53 didn’t” raising concerns of cancer risk in patients.
Throughout its development, the challenges will shift to other areas such as clinical benefit to the patients and commercialization. Determining a reasonable pricing to balance the curative potential of these treatments will be an additional key point to address.
There are also ethical concerns that arise in genome editing to alter human embryos. A Chinese scientist claimed to have helped make the world’s first genome-edited babies in November 2018 by disabling a gene called CCR5 so the twins would develop resistance to potential infection with HIV. This news stimulated an outcry from the global scientific community. The World Health Organization announced the establishment of an international committee to devise guidelines for human gene editing. The first meeting will be held in March 2019.
It’s Only the Beginning
Considering that gene editing is in its infancy, it is difficult to precisely predict its growth prospects. It has been one of the most exciting discoveries of the last decade with its potential to treat human disease. Despite a few hurdles, it is a fast-moving field, and there has already been progress to overcome off-target effects by selecting RNA guides carefully. A deeper understanding in human genome and genetic driver of disease or conditions will likely lead to broader applications for CRISPR-Cas9 technology. In “Human Nature”, a scientific documentary, key scientists involved in gene-editing technology assert that “the biggest tech revolution of the 21st century isn’t digital, it’s biological”. Indeed, this groundbreaking and controversial the gene-editing tool has the potential to fix disease, eradicate cancer, and drive a revolution in the medical community.
“CRISPR/Cas9 in Genome Editing and Beyond”, Wang et al. Annuals Review of Biochemistry 2016
“China’s CRISPR twins: A time line of news”, MIT Technology Review, 2019
“p53 inhibits CRISPR–Cas9 engineering in human pluripotent stem cells”, Ihry et al. Nature Medicine, 2018
“CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response”, Haapaniemi et al. Nature Medicine, 2018
“CRISPR/Cas9 can mediate high-efficiency off-target mutations in mice in vivo” Aryal et al. Cell Death and Disease 2018
CRISPR doc 'Human Nature' embraces the hope and peril of gene editing, Devindra Hardawar, Engadget, March 11, 2019CRISPR TIMELINE, Broad Institute