By Oluwafikayo Ade-Adeleye
The Nobel Prize in Chemistry 2020 was awarded to Emmanuelle Charpentier and Jennifer A. Doudna for the development of CRISPR-Cas9, a method for genome editing. It’s the first time two women will share the prize, and only seven women have ever won it. CRISPR-Cas9, or CRISPR for short, is a very powerful tool that functions like molecular scissors and is able to make precise cuts in strands of DNA, allowing for manipulation or editing of genes. Using these, researchers can change the DNA of animals, plants and microorganisms with very high precision; potentially treating genetic disorders, halting the spread of diseases and improving crops. Nevertheless, the prospect of editing genes calls for very serious and careful ethical considerations.
By 2012, existing methods for gene editing were either too expensive, or slow, or prohibitively difficult to adopt widely. CRISPR, a powerful and easy-to-use tool offers versatility in wide-ranging applications of genome editing, placing it at the fore of advancements in human biology, agriculture, and medicine. In July 2019, CRISPR-Cas9 was used to experimentally treat a patient, a 34-year-old woman with sickle cell disease. Clustered Regularly Interspaced Short Palindromic Repeats or CRISPR (pronounced “crisper”), is a family of DNA sequences found in genomes of some organisms like bacteria. The CRISPR sequence works with an enzyme, Cas9, to recognize and cut DNA strands at targeted points with high precision.
The process is twofold. First, CRISPR-Cas9 has to be programmed to recognise a particular gene in the target DNA, then it should be able to make a cut or edit at that site, a process Doudna says is analogous to using a word processor to fix a typo in a document. A CRISPR sequence is characterised by the presence of nucleotide repeats – DNA sequence that repeats a number of times in a strand of DNA – and spacers. Spacers are unique sequences in-between the nucleotide repeats that help identify target DNA. Scientists are able to use CRISPR to design a guide RNA sequence that will bind to the DNA sequence or gene to be edited. Near this CRISPR location are Cas (CRISPR-associated) proteins that help protect bacteria against viruses. Cas9, which can be easily guided by RNA, is the most popular. CRISPR-CAS9, in essence, is able to combine the Cas9 protein and a guide RNA sequence, and use this to edit specific gene.
When this Cas9-RNA complex is added to a cell, it moves along the DNA strands until it finds and binds to the sequence of the DNA that matches part of the guide RNA sequence. It then cleaves the DNA at that site, causing a double stranded break in the DNA helix. What happens next is the edit, and its outcome depends on how the DNA is repaired. DNA repair occurs naturally and is done by one of two main repair mechanisms. The first method, “non-homologous end joining”, trims the single stranded ends of the broken DNA, and then binds the two ends of the DNA using DNA ligase (molecular glue). This “trimming” however, leads to loss of genetic information resulting in mutations which could disrupt a gene. This is the most common use of CRISPR for gene editing: simply disabling a gene. The other repair mechanism is called “homology-directed repair”. The cell repairs the break by filling in the gap with a sequence of nucleotides using a short strand of DNA as a template. Scientists can supply a custom DNA template, thereby incorporating specific genetic information into the target DNA. In recent years, CRISPR systems have been developed that do not cut DNA, but simply turn genes on or off. Techniques like base editing – changing one letter of the DNA sequence to another – and prime editing, which cuts only one strand of the DNA helix, are gaining popularity.
CRISPR has many benefits over other gene editing methods. Its relatively easy to use in a lab, it’s cheaper, and more precise, making genome editing more commercially accessible and affordable. Consequently, research and development in genome engineering is accelerating at incredible speeds, and scientist now better understand the genetic structures of various organisms and diseases. Experts predict that the CRISPR technology will have wide-reaching impact in agriculture, environmental ecology, and medicine because its ease-of-use has put gene editing at the forefront of research in several fields of biology. In livestock, it has already been used to breed animals with more meat, or thicker fur, and to making them resistant to some diseases that affect livestock, reducing loss for farmers. With crop, scientists now work with the native DNA to enhance yield and drought tolerance, and plants are also being engineered to be bigger and healthier.
More interestingly, CRISPR can be used to correct genetic disorders in embryos (fertilised eggs), and even to choose the genetic endowments of future children. But gene editing is still relatively new. Currently, germline editing – altering the DNA of sperm, eggs, or early embryos — that will result in pregnancies is frowned upon by the international scientific community. Although it could potentially eliminate genetic diseases from family lines, researchers can’t yet guarantee that CRISPR systems make the desired edits all of the time. According to Jennifer Doudna “the technology is just too early-stage and we don’t understand well enough how it works in human embryos.” The potentially far-reaching applications of CRISPR technology raise questions about the benefits and costs of making changes to genomes (what if disabling a gene responsible for one disease makes an individual susceptible to another). Tampering with the germline calls for the introduction of ethical limits as these genes can be passed down for many generations.
Most of the conversation on the ethics of gene editing centres on altering the germline in humans. In 2018, Jiankui He, a scientist in China, modified human embryos that later resulted in the birth of twin girls. His experiment has attracted widespread condemnation. Using CRISPR-Cas9, he tried to make the babies AIDS resistant by altering a specific gene. Gene editing for reproductive purposes is banned in most countries. Before the technology can be adopted, there is need for answers to pertinent ethical and societal questions. For example, who decides that an intervention in an offspring’s genome is necessary? Is it the doctor, or the parent? Some experts argue that such a decision could be a violation of the future child’s fundamental right to personal identity and breaches the dignity of the person as a free and independent human being. Being able to choose an offspring from a number of different versions of that offspring could be highly consequential and a source of uncertainty. Following whatever consequences of the intervention, it becomes impossible to make assumptions about what an alternate life would have been like.
There is the case where editing the genome of a future child could be deemed morally permissible. A situation where a child could suffer from a genetic defect leading to disability, or an inherited disease such as hypertrophic cardiomyopathy or cystic fibrosis, might be deemed as necessitating intervention. There is, therefore, need to clearly distinguish between permissible and non-permissible interventions, as this could serve as the basis for much needed international regulation on gene editing. Any distinctions will likely fall along the lines of ‘therapeutic’ or ‘enhancement’ interventions. However, there is a lot of grey area between the two. Some experts worry that gene editing, once it’s applied for therapeutic uses, will ultimately lead to non-therapeutic and enhancement interventions which is widely seen as controversial. The implications of so-called ‘designer babies’ on the ethos and dynamics of future societies is significant in any discussion regarding the regulation of gene editing.
The world is not yet ready for gene edited babies. CRISPR technology will eventually be adopted for this purpose, but not until technical hurdles, and ethical concerns are resolved. This enormously powerful genetic tool has not only revolutionised life sciences, but offers yet more promise and potential in medicine and agriculture, and will no doubt transform our world. But like other technologies experiencing exponential growth, artificial intelligence, autonomous robotics etc., just how much impact it will have, whether negative or positive, is not yet clear. There is need for patience, scrutiny, and clear guidelines on the application of these technologies. There is hope, however, that current discussions about CRISPR will spark similar conversations in other fields of science where ethical and societal questions remain unanswered.
- Ade-Adeleye, a systems engineer, writes from Lagos.
Leave a Reply