Genome Editing

Context:

Recently, the Government has allowed genome-edited plants without the cumbersome GMO (Genetically Modified Organisms) regulation at the Genetic Engineering Appraisal Committee (GEAC).

Genome Editing

• Genome editing, or genome engineering, or gene editing, is a type of genetic engineering in which DNA is inserted, deleted, modified or replaced in the genome of a living organism.
• Unlike early genetic engineering techniques that randomly inserts genetic material into a host genome, genome editing targets the insertions to site specific locations
  • This tool has opened up various possibilities in plant breeding. Using this tool, agricultural scientists can now edit the genome to insert specific traits in the gene sequence.
• Advanced research has allowed scientists to develop the highly effective clustered regularly interspaced palindromic repeat (CRISPR) -associated proteins based systems.
• This system allows for targeted intervention at the genome sequence. 

What is CRISPR-CAS9?

• As already discussed, CRISPR-Cas9 is a unique technology that enables scientists to edit parts of the genome by removing, adding or altering sections of the DNA sequence.
• CRISPR full form: Clustered Regularly Interspaced Palindromic Repeats.
• CRISPRs are specialized stretches of DNA, and the protein Cas9 (“CRISPR-associated”) is an enzyme that acts like a pair of molecular scissors, capable of cutting strands of DNA.
• CRISPR is a dynamic, versatile tool that allows us to target nearly any genomic location and
  potentially repair broken genes. It can remove, add or alter specific DNA sequences in the genome of
  higher organisms.

How does it work?

• The gene editing tool has two components : 
  1. a single-guide RNA (sgRNA) that contains a sequence that can bind to DNA.
  2. the Cas9 enzyme which acts as a molecular scissor that can cleave DNA.
• In order to selectively edit a desired sequence in DNA, the sgRNA is designed to find and bind to the target.
• The genetic sequence of the sgRNA matches the target sequence of the DNA that has to be edited.
• Upon finding its target, the Cas9 enzyme swings into an active form that cuts both strands of the target DNA.
• One of the two main DNA-repair pathways in the cell then gets activated to repair the double-stranded breaks.
• While one of the repair mechanisms result in changes to the DNA sequence, the other is more suitable for introducing specific sequences to enable tailored repair.
• In theory, the guide RNA will only bind to the target sequence and no other regions of the genome.
• But the CRISPR-Cas9 system can also recognise and cleave different regions of the genome than the one that was intended to be edited.
• These “off-target” changes are very likely to take place when the gene-editing tool binds to DNA sequences that are very similar to the target one.
• Though many studies have only found few unwanted changes suggesting that the tool is probably safe, researchers are working on safer alternatives.

Applications of CRISPR Gene Editing:

• Embryonic stem cell and transgenic animals: CRISPR-Cas systems can be used to rapidly and efficiently engineer one or multiple genetic changes to murine embryonic stem cells for the generation of genetically modified mice. 
• Disease modelling: Disease animal models have been essential resources in advancing the biomedicine field. With the help of genome editing technologies, many applicable models with specific mutations which could mimic clinical phenotypes have been generated.
• Cancer models: With the help of genome editing tools, numerous studies have been carried out through modifying key genes for generating accurate and specific cancer models. Cancer models are the most effective ways to study mutational functions which result in cancer.
• Genome editing technologies are not only used for generating disease animal models but also destined to enter the therapeutic area. There are plentiful means for genome editing based therapy:
  • inactivation or correction of harmful mutations
  • introduction of protective mutations
  • insertion of therapeutic exogenous genes
  • destruction of viral DNA
• Productivity improvement: Continuous decrease in the availability of land and water for agriculture, uncertain weather conditions and a growing population are signals for the urgent need for an alternative approach in the country. In this scenario, scientists are optimistic about the possibilities of genome editing for enhancing crop productivity to overcome the shortcomings of traditional transgenic methods like irregular breeding cycles, lack of precision in intended trait selection and uncertainty in getting desirable mutations.
• Allergy-free food: Food allergies affect a huge percentage of the population and can be life-threatening in some cases. With CRISPR, it could be possible to make milk, eggs or peanuts that are safe for everyone to eat. 
• Greener fuels: Gene editing could improve the production of biofuels by algae. Using CRISPR-Cas9, the company Synthetic Genomics has created strains of algae that produce twice as much fat, which is then used to produce biodiesel. In particular, the gene-editing tool allowed scientists to find and remove genes that limit the production of fats.
• Eradicating pests: CRISPR could help us control the numbers of animal species that transmit infectious diseases or that are invasive in a particular ecosystem. The gene-editing technology can be used to create ‘gene drives’ that ensure a genetic modification will be inherited by all the offspring, spreading throughout an animal population over several generations.

How is Gene Editing different from GMO development?

• Genetically Modified Organisms (GMO) involves modification of the genetic material of the host by introduction of a foreign genetic material.
• In the case of agriculture, soil bacteria is the best mining source for such genes which are then inserted into the host genome using genetic engineering.
  • For example, in case of cotton, introduction of genes cry1Ac and cry2Ab mined from the soil bacterium Bacillus Thuringiensis (BT) allow the native cotton plant to generate endotoxins to fight pink bollworm naturally.
  • BT Cotton uses this advantage to help farmers naturally fight pink bollworm which is the most common pest for cotton farmers.
• The basic difference between genome editing and genetic engineering is that while the former does not involve the introduction of foreign genetic material, the latter does.
• In the case of agriculture, both the techniques aim to generate variants which are better yielding and more resistant to biotic and abiotic stress.
• Before the advent of genetic engineering, such variety improvement was done through selective breeding which involved carefully crossing plants with specific traits to produce the desired trait in the offspring.
• Genetic engineering has not only made this work more accurate but has also allowed scientists to have greater control on trait development.

Significance of Genome editing:

Genome editing is of great interest in the prevention and treatment of human diseases. Currently, most research on genome editing is done to understand diseases using cells and animal models. Scientists are still working to determine whether this approach is safe and effective for use in people. Its significance can be known from the following points:

• Identification: It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, haemophilia, and sickle cell disease.
• Treating complex diseases: It also holds promise for the treatment and prevention of more complex diseases, such as cancer, heart disease, mental illness, and human immunodeficiency virus (HIV) infection.
• Treating disorder: India has a large burden of genetic disorders and unmet medical needs and gene therapy can prove to be a turning point in the treatment of such disorders. 
• Crops and Livestock: The technique of genome editing can also be used for increasing yield, introducing resistance to disease and pests, tolerance of different environmental conditions.
• Industrial Biotechnology: It can be used for developing ‘third generation’ biofuels and producing chemicals, materials, and pharmaceuticals. 
• Biomedicine: Genome editing is also beneficial for pharmaceutical development, xenotransplantation, gene and cell-based therapies, control of insect-borne diseases. 
• Reproduction: It helps in preventing the inheritance of a disease trait. 

What are the cons of Gene editing?

• Making irreversible changes to every cell in the bodies of future children and all their descendants would constitute extraordinarily risky human experimentation.
• There are issues including off-target mutations (unintentional edits to the genome), persistent editing effects, genetic mechanisms in embryonic and fetal development, and longer-term health and safety consequences.
• Some argue that we do not understand the operations of the genome enough to make long-lasting changes to it. Altering one gene could have unforeseen and widespread effects on other parts of the genome, which would then be passed down to future generations.
• Many consider genome alterations to be unethical, advocating that we should let nature run its course.
• Few argue that after permitting human germline gene editing for any reason would likely lead to its ignorance of the regulatory limits, to the emergence of a market-based eugenics that would exacerbate already existing discrimination, inequality, and conflict.
• It will become a tool for selecting desired characteristics such as intelligence and attractiveness.

Concerns in India:

• Poor management: Based on the management of scientific technology in the past, it is uncertain whether or not the current regulatory landscape in India would be capable of enforcing the regulation of such an immensely powerful technology in a safe and ethical manner.
• Mishandling: Past developments in genetic technology have been mishandled, demonstrating the capacity (or lack thereof) of India’s regulatory organisations.
  • For example, take the development of genetically modified crops. While the permissibility of these was still being debated in parliament, they were being illegally and prematurely sown in Gujarat in spades because of their perceived profitability.
• Corruption: This was largely a result of corrupt practices in Indian regulatory agencies. In the medical field, India has even gone so far as to ban the clinical use of stem cell therapy because of “rampant malpractice” and the inability to regulate its commercial use.
• Misuse & manipulation: There is little discouragement of the misuse and manipulation of medical technology for personal or commercial gain.
• Black market for human organs: The extensive growth of black markets for human organs and counterfeit medicine in India is the greatest testament to this statement.

The above issues paint an alarming picture of the state of regulation with regard to medical services in India and raise several concerns when considering the regulation of profitable gene-editing technology.

What are the Regulatory Issues Preventing the Technique?

• Across the world, GM crops have been a topic of debate, with many environmentalists opposing it on the grounds of bio safety and incomplete data. In India, the introduction of GM crops is a laborious process which involves multiple levels of checks.
  • Till date the only crop which has crossed the regulatory red tape is Bt cotton.
• Scientists both in India and across the world have been quick to draw the line between GM crops and genome edited crops. The latter, they have pointed out, has no foreign genetic material in them which makes them indistinguishable from traditional hybrids.
  • Globally, European Union countries have bracketed genome edited crops with GM crops. Countries like Argentina, Israel, US, Canada, etc have liberal regulations for genome edited crops.

The Road Ahead for Genome Editing:

• Current scientific advancements show that CRISPR is not only an extremely versatile technology, but it’s also proving to be precise and increasingly safe to use. But a lot of progress still has to be made.
• At presents, scientists are only beginning to see the full potential of genome-editing tools like CRISPR-Cas9.
• Currently, there are no internationally agreed-upon laws or regulations on gene editing, leaving scientific research and application of CRISPR technology to the discretion of individual countries. An international protocol is the need of the hour.
• For CRISPR-Cas9 genome editing technology to be embraced by the public, it must be applied responsibly. The global research effort must remain focused on treating disease rather than engineering new human traits or creating so-called designer babies.
• According to a recent report, the global gene therapy market is anticipated to reach USD 4,300 million by 2021.
• The demand for gene therapy is primarily driven by continuous technological advancements and successful progression of several clinical trials targeting treatments with strong unmet need.
• Moreover, rising R&D spend on platform technologies by large and emerging biopharmaceutical companies and favourable regulatory environment will accelerate the clinical development and the commercial approval of gene therapies in the foreseeable future.
• Despite the promise, the high cost of gene therapy represents a significant challenge for commercial adoption in the forecast period.
• North America holds a dominating position in the global gene therapy market which is followed by Europe and the Asia Pacific.
• Asia Pacific region shows signs of high growth owing to the booming economies of India, and China.
• Overall, the field of gene therapy continues to mature and advance with many products in development and nearing commercialization.

Conclusion:

The development of CRISPR-Cas proteins for genome editing applications has had a profound impact on biology and biotechnology over the past few years. These tools have democratized the ability to rewrite the information contained in genomes and thereby to both understand and alter genetic traits. The positives and negatives of gene-editing technologies are discussed and disseminated to a great degree. They represent very real, tangible opportunities at positively impacting the lives of various patients with certain diseases. However, it is essential not to generalise this potential across societies and nations, but to recognise that each country is unique and has its own narrative. Going forward, understanding that the technology of gene editing, requires more caution than optimism, regulatory efforts must pause to consider these issues in depth.

In the case of India, it is crucial that new rules and regulations are created to take into account the country’s unique professional and sociocultural landscape and, in addition, it’s capacity for ensuring that such a technology is handled responsibly and ethically.

Source: Indian Express

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