By Evan Li
Genes are the basic unit of heredity; they serve as the instructions from which RNA is transcribed and subsequently, proteins are translated. However, not all genes code for proteins. Genes are composed of segments of DNA, linked together in the DNA sequence, but they can vary widely in size, from around a few hundred base pairs to almost 2 million base pairs. DNA sequences contain many genes; the human genome is thought to contain between 20,000 and 25,000 genes. Until recently, editing a genomic sequence was thought to be entirely impossible; that was before the discovery of the CRISPR genes.
CRISPR is an acronym that stands for “Clustered Regularly Interspaced Short Palindromic Repeats,” and are repetitive DNA sequences observed in bacteria. It was discovered that these sequences matched viral sequences exactly and that in the case of viral infection, would be transcribed into RNA. Scientists observed that these RNA would guide nucleases to the viral sequences, which would cleave the sequences, deactivating the viruses and protecting the bacterial cell.
In 2012, researchers, Jennifer Doudna and Emmanuelle Charpentier discovered that the CRISPR gene could be programmed to edit any DNA sequence, as long as it was guided by a guide RNA or gRNA. It was considered one of the most significant discoveries in the history of biology and the researchers received Nobel Prize in Chemistry in 2020 for their work. This remains the only Nobel Prize ever awarded to two women.
Doudna and Charpentier developed a technique that allowed a gRNA to guide the CRISPR/Cas9 (CRISPR-associated) nuclease to cleave at 2 specified parts of a DNA sequence to cleave out an entire gene or an association of genes within a cell. With this process, if a DNA template is included with the CRISPR technology, the cell can insert a ‘corrected’ gene in the place of the deleted gene, or insert one that is entirely new to the DNA sequence.
Scientists quickly noticed that this process makes it possible to fix genetic/hereditary diseases, by replacing faulty genes that would otherwise cause damage to the individual. The first CRISPR gene therapy trials began in 2019 with sickle cell anemia patients in the US. Patients had their bone marrow blood cells harvested, then edited with CRISPR/Cas9 technology to produce fetal hemoglobin, and had these cells reinjected into their bodies. The trial was a resounding success. Scientists had hoped that around 20% of hemoglobin in their systems would be fetal hemoglobin, yet many patients have far exceeded that percentage of fetal hemoglobin. Victoria Gray, one of the patients who received the treatment, said in an NPR interview that her treatment had revolutionized her life, calling it “the change I’ve been waiting on my whole life”. In 2020, a trial was conducted to correct a gene causing blindness while the cells were still inside patients. This trial was also considered a groundbreaking success. Further studies have shown CRISPR technology is capable of treating many hereditary diseases, which are not limited to hemophilia, β-thalassemia, cystic fibrosis, Alzheimer's, Huntington's, Parkinson's, tyrosinemia, Duchenne muscular dystrophy, Tay-Sachs, and fragile X syndrome disorders.
However, regardless of how exciting these results may be, there is a multitude of ethical issues surrounding CRISPR gene editing. Many scientists have cited safety concerns, as CRISPR/Cas9 can potentially cut DNA sequences in the wrong positions or multiple positions. Those that have researched germline editing (gene editing of human embryos) have claimed the process is never better than pre-diagnosis of genetic disorders or in-vitro fertilization. Others have stated that CRISPR therapy is never able to achieve informed consent, since those affected by edits are often embryos and future generations.
Legal cases involving CRISPR gene editing have already begun. A scientist in China, He Jiankui, was sentenced to 3 years in prison for creating the first genetically modified babies, whose embryos had their genomes edited. His procedure stirred worldwide controversy on if gene editing should ever be used for reproductive purposes. In 2022, Hu was released from prison and vowed to continue researching gene therapy for rare genetic diseases. In many nations including the US and EU, embryo genome editing is illegal as the procedure has been deemed too risky for reproductive purposes. Research on human embryo editing cannot receive federal funding in the US, but in many other nations research is permitted.
For now, the world seems divided on how genome editing should be used in the future. There are exciting clinical results that have prompted scientists to conduct more research on the potential benefits, but there are also glaring ethical issues that researchers constantly grapple with.
References:
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