Treating HEREDITARY Diseases with the Nobel Prize-Winning CRISPR Gene Editing Technique

Known as genetic scissors and the subject of the 2020 Nobel Prize in Chemistry, the highly precise and practical gene editing technique CRISPR is advancing, ushering in the era of correcting germline (hereditary) genetic damage.

Fast, accurate and easy-to-use CRISPR-Cas9 has made genomic editing more efficient; it has also made human germline (hereditary, transmitted through sperm and egg cells) editing much more feasible. In addition, precise/point editing has reduced many of the ethical barriers created to prevent editing their genes and concerns. 

The co-director of the Institute for Practical Ethics at the University of California, San Diego, Dr. John H. Evans, writes, "The ethical debate over what is called human gene editing has been going on for more than 50 years". "For almost all of that time, there has been a consensus that there is a moral distinction between somatic and human germline editing."

Note: Research conducted alongside mapping the human genome has found that most of the damage that causes cancer ( mutations ) occurs in body, or somatic, cells. Such mutations are called somatic mutations. In other words, this damage is not passed to offspring through inheritance. However, mutations that occur in reproductive cells, although few, are passed to offspring and increase cancer risk. Such mutations are called germline / hereditary mutations.

• Related topic: Familial, Hereditary and Sporadic: Frequently Confused Concepts in Cancer

Expectations of science are high in genetic diseases – ethical debates should soften

In Proceedings of the National Academy of Sciences ( PNAS ), Evans argues in an article that many of the strong bioethical arguments that once made germline editing a detailed concept have begun to unravel in the CRISPR era.

Evans and a growing number of other ethicists argue that the moral divide that has long separated scientific thinking about germline and somatic cell editing has visibly weakened.

The announcement made in 2018 by He Jianqui, who genetically modified human embryos through CRISPR in China and produced twins known as Lulu and Nana, caused serious concern worldwide and helped strengthen policies on germline gene editing. Despite the scorn directed at him around the world for his brazen human experiment, his research also helped open the door to a more moderate view of manipulating germline genes. Policymakers followed guidelines on the feasibility of research involving hereditary genes in a softer tone. It appeared that a rapidly growing number of scientists were interested in developing potential treatments by manipulating genetic sequences in germline DNA.

Evans in PNAS wrote: "At present, in the mainstream US and UK bioethical debate that has the greatest influence on science policy, the somatic/germline distinction has lost its strength. China led the Second International Summit on Human Germline Editing despite the birth of germline-modified children, and held similar views that germline intervention is acceptable in principle as long as CRISPR is safe and the protection of human subjects is observed."

A new class of treatment has emerged: genomic editing

Genomic editing actually refers to several genetic technologies that allow scientists to "rewrite" parts of an organism's genetic code. DNA sequences can be deleted, receive insertions or be altered at almost any genomic location. Unlike other genomic editing technologies, CRISPR-Cas9 is faster, more efficient and easier to use. And, as biologists increasingly say, CRISPR has opened a new horizon of possibilities for what can be achieved with a powerful biological tool.

This time it is not an invention, but "a profound observation"

Although CRISPR looks like high technology, it was not invented in a laboratory. The editing technique is actually an adaptation of a naturally occurring genome editing system found in bacteria and archaea. These organisms take literally infinitesimal sequences of genetic material from viruses that invade them and then use these captured sequences to create DNA segments called CRISPR sequences.

These repetitive sequences (genetic fragments), called CRISPR, allow bacteria and archaea to remember viruses in case of future invasion. When viruses (bacteriophages) attack again, the bacterium or archaeon produces RNA from the CRISPR sequences, zeroing in on viral genes. Bacteria and archaea then rely on an enzyme called Cas9 to cut up viral genes, effectively destroying the virus. In many ways, this ability to remember infectious viruses means a more primitive immune system, which, compared with the much more complex mammalian immune system, acts in a similar way to the memory B and T cells of the latter.

Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier of the Pasteur Institute in Paris, through their joint work involving CRISPR-Cas9, were awarded the 2020 Nobel Prize in Chemistry. The technology was first developed and named by Spanish biologist Francis Mojica, a professor at the University of Alicante in Spain, but he was not included as a recipient of the prize.

Meanwhile, Evans underlines that when CRISPR emerged as a powerful laboratory tool in the early 2010s, the misconception that "germline modification would always be impossible" prevailed.

Evans said, "After it became clear that some scientists were trying to use CRISPR to modify human embryos in the laboratory, many scientific groups published documents on human germline editing, mostly advocating doing no harm."

For example, according to Evans, in August 2015 the American Society of Gene and Cell Therapy and the Japan Society of Gene Therapy took a stance against gene editing or gene modification in human embryonic cells because of "safety and ethical concerns" regarding human germline editing.

The first human experiments using CRISPR for treatment have begun

The first human clinical trials using CRISPR have begun. A team of researchers from Intellia Therapeutics and Regeneron Pharmaceuticals conducted the first clinical trial involving in vivo CRISPR human "somatic" gene editing. In The New England Journal of Medicine, the group described in their published article developing a CRISPR technique to treat patients with transthyretin amyloidosis (ATTR amyloidosis) and, in a phase 1 clinical trial, administering a treatment called NTLA-2001 to six patients. The results of this small study are promising.

Conclusion

Despite ethical concerns, with the CRISPR revolution gene editing has begun to be applied in human cells, plants and animals. The initially firm stances and concerns have begun to soften. This is because CRISPR has the potential to provide substantial benefits in the management of germline (hereditary) diseases that affect millions of people worldwide every year.

The first gene editing clinical study in humans involves somatic gene editing. This treatment is on its way to being successful. The most important question here is "how long gene editing will last." Gene changes can remain stable for up to 1 year in mice, but this has never been tried in humans before. The results at 28 days are positive. There are concerns about germline editing. There is no common guideline. A very clear practice guideline must be established, and scientists and bioethicists are working on this. A definitive treatment for hereditary diseases appears possible only through germline genome editing.

As genetic tools become increasingly powerful, we should focus on why we use the tools and on "what can be done should be done."