The era of CRISPR therapeutics is here (GS paper 3, Science and Technology)
Why in news?
- The world of medicine is currently abuzz with news of regulatory agencies’ approval for two highly anticipated CRISPR-based therapies for sickle-cell disease and thalassaemia in the U.K. and the U.S.
- The approval is groundbreaking because it signals an era that could transform the lives of millions of patients and families grappling with these inherited blood disorders.
The discovery of the CRISPR system:
- Clustered regularly interspaced short palindromic repeats (CRISPR) are DNA elements that Spanish researchers discovered in archaea in 1993, and named and described later in a number of bacterial genomes.
- These elements contain pieces of genetic material derived from viruses that infect bacteria (for example, bacteriophages) and a set of proteins called Cas, or CRISPR-associated.
- Researchers tried to explain the elements’ effect on antiviral immunity in 2005, but later found that CRISPR + Cas proteins could detect and prevent viral infections. That is, the two formed an antiviral defence system and helped bacteria ‘acquire’ resistance.
- Then, in 2010, scientists demonstrated that CRISPR + specific proteins called Cas9 had the ability to cut double-stranded DNA at specific points. They also found the RNAs molecules that guided the Cas9 proteins to specific positions on a genome.
- In 2012, researchers figured out a way to create synthetic RNA that could bind to Cas9 and guide it to a specific point on a DNA, where it could edit the DNA.
- This pathbreaking work came from the labs of Emmanuelle Charpentier and Jennifer Doudna, and they were awarded the 2020 Nobel Prize in Chemistry for it.
Progress:
- A study suggested that Cas9 could be targeted to specific genome locations by crispr RNA (crRNA).
- In all, the researchers demonstrated the utility of the CRISPR-Cas9 system as a programmable ‘molecular scissor’ that could cut in DNA at a chosen spot with unparalleled accuracy. The specific spot could be picked by modifying the crRNA accordingly.
- Another teams showed that CRISPR-Cas9 could be used to edit the genomes of eukaryotic organisms.
- This innovation has since spurred a myriad applications, from targeted genetic therapies to agricultural advancements.
CRISPR in medicine:
Casgevy:
- In November 2023, the national regulator in the U.K., the Medicines and Healthcare products Regulatory Agency (MHRA), approved the use of a CRISPR-based method called exagamglogene autotemcel sold under the brand ‘Casgevy’ to treat sickle-cell disease and transfusion-dependent -thalassemia.
- The approval came after the MHRA evaluated safety and efficacy data in an ongoing clinical trial in 29 and 42 patients respectively.
- In close succession, the U.S. Food and Drug Administration also approved Casgevy to treat sickle-cell disease, rendering it one of the first CRISPR-based therapeutics to be approved by two major drug regulators.
First-generation technologies:
- In Casgevy, a patient’s blood stem cells are extracted, their genes modified to remove the defect that produces the sickling, and regrafted back. These cells then proliferate to produce normal red blood cells. The approvals come full circle 74 years after Linus Carl Pauling described the disease as a molecular disorder.
- While researchers have developed drugs to treat the symptoms of the disease, Casgevy’s approval signals their ability now to fix its molecular basis.
- They are all based on what researchers call first-generation technologies.
New applications:
- CRISPR-based clinical technologies have grown to become more efficacious as well as efficient, with a panoply of new applications and specificities.
Base-editing:
- One fascinating approach is called base-editing, where scientists edit genomes at the resolution of a single nucleotide (DNA is a polymer consisting of multiple nucleotides chained together).
- Recently, Verve Therapeutics announced results from an important clinical trial it has been conducting to test a base-editing approach to treat familial hypercholesterolemia, another prevalent and oft-undiagnosed genetic disease.
Prime editing:
- Another emerging technique is prime editing, where researchers use a search-and-replace strategy to directly write or insert specific sequences into an existing genome with high accuracy.
Modifying epigenetic effects:
- A fourth example is of systems that use CRISPR to modify epigenetic effects (effects of a body’s environment on its genes) in targeted fashion.
Way Forward:
- None of these technologies are without caveats. Researchers have already reported several safety and accuracy issues. An important one is off-target events: where a CRISPR-Cas9 system becomes inaccurate and edits some other part of the genome, with unintended consequences.
- So while there is enormous potential for these technologies, the risk needs to be balanced with both short- and long-term benefits. Many of these therapies are also too early in their development cycle.
- Casgevy et al. mean for the millions of people suffering from genetic diseases, including those whose molecular mechanisms remain unknown.
An overview of the European Union’s Artificial Intelligence Act
(GS paper 3, science and Technology)
Context:
- The European Union’s Artificial Intelligence (AI) Act is a significant legislative initiative aimed at regulating artificial intelligence technologies within the EU.
- The objectives of the EU AI Act are to create a regulatory framework for AI technologies, mitigate risks associated with AI systems, and establish clear guidelines for developers, users, and regulators.
- The act aims to ensure the responsible use of AI by protecting fundamental rights and promoting transparency in AI applications.
Strengths of the Act
Risk bases approach:
- One of the notable strengths of the EU AI Act is its risk-based approach. The legislation categorises AI applications into different risk levels, ranging from unacceptable to low. This approach enables tailored regulations, with higher-risk applications subject to more stringent requirements.
- This flexibility acknowledges AI technologies’ diverse potential impact on society. It also explicitly prohibits certain AI practices deemed unacceptable, such as social credit scoring systems for government purposes, predictive policing applications, and AI systems that manipulate individuals such as emotional recognition systems at work or in education.
- This prohibition reflects the EU’s commitment to preventing the misuse of AI technologies.
Transparency and accountability:
- The EU AI Act emphasises transparency and accountability in AI development and deployment.
- It requires developers to provide clear information about the capabilities and limitations of AI systems, enabling users to make informed decisions.
Regulatory oversight & Assessment:
- The legislation mandates that developers maintain comprehensive documentation to facilitate regulatory oversight.
- Moreover, to ensure compliance with the regulations, the EU AI Act introduces the concept of independent conformity assessment.
- Higher-risk AI applications like medical devices, biometric identification, and access to justice and services, must undergo assessment processes conducted by third-party entities.
- This approach enhances objectivity and reduces the risk of conflicts of interest, contributing to the credibility of the regulatory framework.
Limitations:
- One of the criticisms of the EU AI Act is the challenge in accurately defining and categorising AI applications. The evolving nature of AI technologies may make it difficult to establish clear boundaries between different risk levels, potentially leading to uncertainties in regulatory implementation.
- Critics have also argued that the stringent regulations in the EU may hinder the competitiveness of European businesses in the global AI market.
- While the Act aims to ensure ethical AI practices, some fear that overly restrictive measures could stifle innovation and drive AI development outside the EU.
- Additionally, compliance with the EU AI Act may impose a significant burden on smaller businesses and start-ups.
- The resources required for conformity assessments and documentation may disproportionately affect smaller players in the AI industry, potentially limiting their ability to compete with larger, more established counterparts.
- Striking the right balance between regulation and fostering innovation is crucial, with critics arguing that the EU AI Act may lean too heavily towards stringent controls.
The potential implications:
- The EU AI Act is likely to have a global impact, influencing the development and deployment of AI technologies beyond the EU’s borders. As a major economic bloc, the EU’s regulatory framework may set a precedent for other regions, shaping the trajectory of AI development on a global scale, just like the MiCa regulation did for crypto-assets.
- By prioritising ethical considerations and fundamental rights, the EU AI Act contributes to the establishment of global norms for AI development. The impact on innovation and competitiveness will depend on the balance struck by the EU between regulation and fostering a conducive environment for AI development.
- It encourages collaboration and cooperation between regulatory authorities, fostering a unified approach to AI regulation. International collaboration in regulating AI technologies is essential to address global challenges and ensure consistent standards across borders.
Implementation:
- Any individual has the right to report instances of non-compliance. The EU member states’ market surveillance authorities will be responsible for enforcing the AI Act. There will be specific limits on fines applicable to small and medium-sized enterprises (SMEs) and start-ups.
- The EU will establish a centralised ‘AI office’ and ‘AI Board.’ In case businesses do not adhere to the EU AI Act, fines could range from $8 million to almost $38 million, depending on the nature of the violation and the company’s size.
- For instance, fines may amount to up to 1.5% of the global annual turnover or €7.5 million for providing incorrect information, up to 3% of the global annual turnover or €15 million for general violations, and up to 7% of the global annual turnover or €35 million for prohibited AI violations.
Way Forward:
- The EU’s AI Act represents a significant step towards regulating AI technologies responsibly and ethically. While it addresses key concerns associated with AI, such as transparency, accountability, and risk mitigation, there are challenges and potential drawbacks that need careful consideration.
- The global impact of the EU AI Act and its potential to shape international norms make it a landmark initiative in the ongoing discourse on the responsible development and deployment of artificial intelligence.
