Gene Editing

20 Now that we can - should we? Gene Editing

“Your scientists were so preoccupied with whether or not they could, they didn’t stop to think if they should”. 25 years on, this quote from Jurassic Park by the great Jeff Goldblum rings truer than ever. While every great scientific advance‐ment experiences some level of discussion and controversy, no field attracts more debate than that of human genetic en‐gineering. The development of Clustered Regularly Inter‐spaced Short Palindromic Repeats (CRISPR)-Cas9 gene editing technology has prompted more dispute than poten‐tially any other biological technologies. Never before have we had the ability to so easily and effectively change the hu‐man genome—for better or for worse. CRISPR-Cas9 is for‐cing scientists, governments and the general public to assess the potential consequences of gene editing technology. Are we as a society ready to grapple with the questions gene edit‐ing forces us to consider: should all perceived disabilities be cured? Will the likely cost of gene editing widen social in‐equalities? Are we ready to be able to control human evolu‐tion rather than leaving it to chance ? CRISPR-Cas9 is a gene editing technique that allows for any region of the human genome to be specifically targeted and edited. The field of gene editing was revolutionised. Gene editing experiments were now quicker, cheaper and much more efficient. While the vast majority of researchers used CRISPR-Cas9 to understand the basic functions of genes or to target a specific disease-associated gene, there are several researchers whose experiments fall in a more ethical grey area.

Human Germline Modification (HGM) is the deliberate alteration of human eggs, sperm or embryos which will affect not only the individual in question, but all future generations of the said individual. From the moment CRISPR-Cas9 technology was released, scientists were well aware that this leap forward in technological potential warranted a further debate on societal consequences of HGM both positive and negative. Thus, the first International Summit on Human Genome Editing was held in 2015. It was hosted by the Chinese Academy of Sciences and the UK's Royal Society and the scientific and ethical issues associated with human gene-editing research were discussed. A group of global ex‐perts cautioned that HGM could profoundly ‘alter future hu‐man societies’, and ‘exacerbate existing inequalities in society’. Though not against the idea that CRISPR-Cas9 could be used as a preventative treatment for genetic diseases, “Are we as a society ready to grapple with the questions gene editing forces us to consider?”

What is CRISPR-CAS9? Deoxyribonucleic acid (DNA) is a long thin molecule shaped like a double helix. DNA contains all the information needed to create an organism. This information is in the form of a code made up of 4 nucleotide bases called adenine(A), thymine(T), cytosine (C), and guanine(G). The cell 'reads' this code and transcribed to RNA (a single strand of nucleotides). RNA is then translated into amino acids which makes up all the proteins that a cell needs.

Similar to the way that letters combine to form words, DNA bases combine in specific sequences to make genes. For example, eye colour is controlled by sixteen different genes. Small changes in the genetic code, called mutations, can sometimes occur. These are usually harmless. However, there are also many diseases caused by mutations in critical genes. These include mutations in the CFTR gene, causing Cystic Fibrosis, and in the BRCA gene, which greatly increases the risk of developing breast cancer.

CRISPR therapy can treat Sickle Cell Anaemia. Healthy red blood cells carry oxygen around the blood via haemaglobin.

However, in patients with Sickle Cell Anaemia - mutated heamoglobin leads to misshapen blood cells which clump together causing anemia and severe pain.

Scientists use CRISPR-Cas9 technology to reactivate fetal haemoglobin, restoring the normal shape of red blood cells and reducing symptoms. Similar clinical trials using CRISPR technlogy to target cancer and blindness are currently underway. Perspective

CRISPR-Cas9 is made up of the enzyme Cas9 and a length guide-RNA (gRNA).

Cas9

A specific genetic sequence on the gRNA guides Cas9 to a specific gene. gRNA

Cas9 acts like molecular scissors and creates a break in the DNA, which can disable the gene and stop it working. CRISPR-Cas9 can be used to repair a dysfunctional gene by introducing a new piece of DNA with the correct sequence which inserts between the two breaks caused by Cas9.

CRISPR is continuously improving but...

CRISPR-Cas9 is not 100% efficient so not all cells may be edited.

Different genes can have similar DNA sequences. This could cause Cas9 to be directed to the wrong gene.

CRISPR editing of embryos is highly controversial.

“Designer babies” are children who have been genetically edited, particularly with regard to traits such as intelligence, athleticism and appearance.

Creating “designer babies” by editing the genes of embryos is very controversial, as it impacts every cell in the body and all descendants.

Most scientists agree to gene editing for fatal or incurable genetic disorders. However, some scientists believe that there should be no restrictions on which genes can be edited. At the International Summit on Human Genome Engineering, international experts generated guidelines for use of CRISPR-Cas9 including the recommendation to not genetic edit any embryos until both technical and ethical issues had been addressed. Dr He Jianku disregarded the recommendations of the summit and create the worlds first genetically engineered children in November, 2018.

the report from the conference was cautious. It stressed that at the time in question it ‘would be irresponsible to proceed with any clinical use … unless and until (i) the relevant safety and efficacy issues have been resolved … and (ii) there is broad societal consensus about the appropriateness of the pro‐posed application’. Despite the clear advantages CRISPRCas9 has over previous gene editing techniques, not all safety and technological hurdles have been overcome. Though HGM was not banned, the conference recommended that a voluntary moratorium be put in place until the aforemen‐tioned issues were resolved. Broad societal consensus had not and has not been reached with regard to gene editing-based therapies, and regarding non-disease associated gene editing, there is even less consensus.

Announced days before the second International Summit on Human Genome Editing, the scientific community was shocked on the 28 November 2018 when Dr. He Jiankui an‐nounced the birth of the first CRISPR-Cas9 gene-edited children, twin girls called Nana and Lulu. Dr. He disabled the CCR5 gene, which the HIV virus uses to enter and infect cells. Dr. He’s experiment was met with nearly universal condemnation, with scientists labelling his experiments pro‐foundly disturbing and monstrous. Dr. He is not the only researcher pushing the ethical boundaries of gene editing. Dr. Denis Rebrikov, a Russian scientist, has announced plans to carry out similar experiments to Dr. He’s in children at risk of contracting HIV in utero. But it is Dr. Rebrikov’s other planned experiments that capture the ethical complex‐ities of gene editing. He has revealed plans to prevent deaf‐ness in children born to deaf couples using CRISPR-Cas9. While deafness is classified as a disability, the line between disability and diversity is becoming increasingly lax. Many deaf individuals feel that curing deafness would rob them of the rich world of deaf culture and that attempting to “cure” deafness is belittling and immoral. They are not the only ones to feel this way. Those with conditions such as dwarfism or autism hold a similar view. This raises a serious question— should such conditions be cured or should the focus be on increasing accessibility and societal acceptance? Targeting these conditions as something that needs to be fixed could re‐inforce social stigma and is uncomfortably close to eugenics (promoting the improvement of inherited human traits through intervention).

For some, the holy grail of gene editing technology is the infamous designer babies. Human embryos would be edited in order to create a more advanced individual, particularly with reagrd to traits such as intelligence, height or athleti‐cism. Though we neither have the technology to achieve this level of gene editing, nor do we know all the genes involved in the desired traits, it is imperative that the ethics and limits of “designer babies” be established before we can do it. It is likely that HGM—whether carried out via CRISPR-Cas9 or other methods—would be extraordinarily expensive and therefore restricted to those who could afford it. This would prohibit CRISPR-Cas9 technology from being spread equally across all socioeconomic brackets, potentially creat‐ing a genetic aristocracy associated with better health, higher skills and longer life. This would widen existing socioeco‐nomic inequalities.

And what about the designer babies themselves—would the biological advantages given to them correspond to a sim‐ilar social advantage? Some people are naturally gifted in cer‐tain areas and this is applauded and celebrated. But what if someone was born genetically enhanced for speed and won gold in the Olympics—would this be celebrated or con‐demned?

Furthermore could gene editing technology force us to decide on what we consider true humanity? Evolution (the change in a population over successive generations) can in‐troduce drastic changes to a population, but these changes can take thousands if not millions of years. Evolution is an inherently random process highly influenced by environ‐ment. Advancements in gene editing allow for a more selfguided approach as well as significantly speeding up the rate of change. Could we end up changing swathes of the popu‐lation so much that they are seen as inherently different from humans—and if so, what would these changes be?

There are no inherently right or wrong answers to these questions, nor can they be answered by one person. The eth‐ical and societal consequences of gene editing technology are far-reaching and will require worldwide discussion and col‐laboration in order to reach a satisfactory conclusion that will harness the extraordinary potential of gene editing while pro‐tecting us from ourselves. Emma Mee Hayes is studying for a DPhil at the Nuffield Department, at St Edmund Hall. “The ethical and societal consequences of gene editing technology are farreaching and will require worldwide discussion and collaboration...”