When five-year-old Suraj was debilitated with a persistent fever, his family took him to the district hospital in Nuapada in western Odisha. The hospital directed them to the Veer Surendra Sai Institute of Medical Sciences and Research at Burla in Sambalpur, around 250 km from their village. At the Institute, Suraj underwent a diagnostic test called haemoglobin electrophoresis to detect whether he had sickle cell disease (SCD). When the tests confirmed SCD, the Institute registered him as a patient and referred him to Nuapada district hospital for blood transfusions.

Suraj’s story came up during our work with the National Human Rights Commission in 2019. It provides a glimpse of the difficulties that people like Suraj, from marginalised tribal communities, face even to access basic healthcare and diagnostics.

It is, however, the beginning of an arduous battle with an under-resourced health system, inadequate information, and high expenditure.

In light of these realities, and the global discussion on advances in human genome editing, the question that becomes especially pertinent is whether these conversations allow for and are cognisant of such experiences.

SCD is an inherited haemoglobin disorder in which red blood cells (RBCs) become crescent- or sickle-shaped due to a genetic mutation. These RBCs are rigid and impair circulation, often leading to anaemia, organ damage, severe and episodic pain, and premature death. India has the third highest number of SCD births, after Nigeria and the Democratic Republic of the Congo. Regional studies suggest approximately 15,000-25,000 babies with SCD are born in India every year, mostly in tribal communities. 

Per the 2023 ‘Guidelines for National Programme for Prevention and Management of Sickle Cell Disease’, of the 1.13 crore persons screened in different states, about 8.75% (9.96 lakh) tested positive. It is also one of the 21 “specified” disabilities listed in the Schedule of the Rights of Persons with Disabilities Act 2016.

Access to treatment as a major issue

In 2023, the Government of India launched the National Sickle Cell Anaemia Elimination Mission, to eliminate SCD by 2047. At present, however, treatment and care for SCD remains grossly inadequate and inaccessible. States with a high prevalence of SCD, particularly among their most marginalised populations, are falling behind in their efforts to reach out and provide basic care to those affected.

An apposite example is the (un)availability of the drug hydroxyurea. It lessens the severity of pain, reduces hospitalisations, and improves survival rates by increasing the size and flexibility of RBCs and lowering their likelihood of becoming sickle-shaped. Yet States are largely unable to provide hydroxyurea for SCD patients, pointing to their inability to purchase, stock, and distribute this drug. Even though the National Health Mission’s Essential Medicines List requires the drug to be availed at the primary healthcare level, hydroxyurea is currently only available in certain tertiary-level facilities, such as medical colleges.

Blood transfusion is another important therapy for SCD, but its availability is limited to district-level facilities. Most block-level community health centres don’t offer them. Even during an emergency, families of SCD patients have to arrange for blood replacement units and pay for expensive private transport. Pain medications, from painkillers to non-steroidal anti-inflammatories and opioids, are also scarce.

Bone marrow transplantation (BMT), until recently the other cure for SCD, is out of reach for most SCD patients due to the difficulty in finding matched donors, the high cost of the treatment at private facilities, and long waiting times in public hospitals. There have been efforts in some states to improve public health facilities but it remains to be seen how successful they are at making care universally available.

Access to and equity of CRISPR

In light of this, the application of the gene-editing technology called CRISPR (short for ‘Clustered Regularly Interspaced Short Palindromic Repeats’) to treat SCD is important – for its novelty and promise but also for the health disparities it makes apparent.

The U.S. Food and Drug Administration recently approved two gene therapies, Casgevy and Lyfgenia, to treat SCD in people ages 12 and older. Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics and also approved in the U.K., is the first CRISPR-based therapy to have received regulatory approval in the U.S. Lyfgenia, manufactured by Bluebird Bio, doesn’t use CRISPR but depends on a viral vector to change blood stem-cells.

Both treatments entail collecting a patient’s blood stem-cells, modifying them, and administering high-dose chemotherapy to destroy the damaged cells in the bone marrow. The modified cells are then infused into the patient through a hematopoietic stem cell transplant. The treatments are expected to take up to a year and require several hospital visits. Victoria Gray, a patient in her mid-30s from the U.S., was the first recipient of Casgevy in clinical trials. Having been free of SCD symptoms and pain for a few years, she is now seen as a symbol of hope for new therapies.

CRISPR’s inventors have won a Nobel Prize and it is celebrated as a revolutionary innovation, but its treatment cost of $2–3 million keeps it out of reach of most of those affected in countries where SCD is endemic. While researchers and policymakers are considering potential alternatives to improve access in low- and middle-income countries, such high-tech therapies require advanced care in well-resourced hospitals, too, bringing with it challenges of availability, affordability, and quality – which disproportionately affect the poor and marginalised. It raises pressing questions about equity, access, and justice in the use of gene therapies.

CRISPR in India

In India, CRISPR’s possible medical applications also pose ethical and legal quandaries. The National Guidelines for Stem Cell Research 2017 prohibit the commercialisation of stem cell therapies and allow the use of stem cells only for clinical trials, except for BMT for SCD. Gene-editing stem cells is allowed only for in-vitro studies. The Guidelines also encourage (but don’t mandate) the sharing of financial benefits resulting from the commercialisation of stem cell products with the donor or community.

Further, the National Guidelines for Gene Therapy Product Development and Clinical Trials 2019 provide guidelines for the development and clinical trials of gene therapies for inherited genetic disorders. India has approved a five-year project to develop CRISPR for sickle cell anaemia. Under its Sickle Cell Anaemia Mission, the Council of Scientific and Industrial Research is developing gene-editing therapies for SCD. Around Rs 34 crore has been allocated for this mission over 2020-2023. It is reportedly in the pre-clinical stage, with clinical trials awaited.

However, the Guidelines need a stronger health inequity and discrimination perspective, addressing issues such as equitable opportunities for underserved populations to safely participate in clinical trials, and whether and how this therapy will be made available to those populations in future.

Adopting and promoting advanced therapies like CRISPR in India require a comprehensive approach that accounts for inequities and disparities in the country’s overall healthcare access framework. While such advances in curative treatments are encouraging, our concerns are primarily focused on the importance of equity and access throughout the lifecycle of research, development, and implementation of gene therapies.

The development of therapeutic technologies occurs at a pace and level that renders it unavailable to the same constituencies most affected by the disease. The wait for the products of gene-editing to trickle down to the margins is long and often in vain. We suggest investment in expensive therapeutic technologies need to be preceded by focused efforts to first make basic treatment available – such as an uninterrupted supply of hydroxyurea – to those direly in need of treatment.

Deliberations on regulatory frameworks also need to be expanded from closed scientific circles to the larger public. Policies on the development of such technologies need to receive inputs from civil society and patients’ advocacy groups to be able to develop frameworks for ethically responsible research. The need of the hour is an approach that focuses on integrating these multiple issues of access to diagnostics, drugs, health information and community support. It is only then that children like Suraj will be able to live a healthy life in the long term.

Sarojini Nadimpally, Gargi Mishra, and Keertana K. Tella work on public health, bio and reproductive technologies, human rights and gender.

“We will each write a ghost story”, said Lord Byron; and his proposition was acceded to. And so on a cold and rainy supposedly summer night in 1816, four friends inspired by German ghost stories, gathered to write one. Among them, a young Mary Shelley, consumed by the idea of creating a story that would “curdle the blood” of her readers, ended up with a novel titled Frankenstein.

With Frankenstein 200 years in the past, the possibility of creating such life is a reality. With the first gene editing technology securing approval for the treatment of sickle cell anemia and beta-thalassemia, we transcend into a new revolutionary phase. The possibilities are endless.

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Casgevy and Lyfgenia, the two cell-based gene therapies approved by the Food and Drug Administration (FDA) for sickle cell anemia treatment and beta-thalassemia utilise the Nobel-winning CRISPR/Cas 9 genome editing technology.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), a feature of the bacterial immune system, forms the basis for this technology. In a nutshell, the system in bacteria serves as a warehouse for past infections by storing a part of the viral genetic material and incorporating it into its own, so the next time it is attacked, the bacteria is capable of recognising the virus and destroying it. The bacteria, in short, is immunised when it employs the CRISPR system. The CRISPR-Cas system is effective and easy to manipulate. Researchers have adapted it as a tool to cut, delete, or add DNA sequences at precise locations, opening different windows to treat genetic disorders, develop drought-resistant plants, modify food crops, or experiment with de-extinction projects involving the woolly mammoth and the dodo.

Sickle-cell anemia (SCA) is an inherited disorder where red blood cells contort to a sickle or crescent shape because of defective hemoglobin, restricting its ability to carry oxygen. According to an article published in the Indian Journal of Medical Research over 20 million people live with SCA in India and it is predominantly seen in the scheduled tribes (ST) and scheduled caste (SC) populations where the majority are economically backward.

Also Read: Explained | How is India addressing sickle cell anaemia? 

Casgevy costs 2.2 million US$ per patient to treat sickle-cell anemia. Indian researchers are working on indigenous treatment involving CRISPR genome editing to reduce the cost. “For India, the issue of pricing is a very important consideration, since it impacts equitable distribution. It is little early to determine now, if production costs can be reduced, or there can be alternative pricing models, or coverage through healthcare, insurance, negotiations with pharma sector, policies around commercialisation for sustainable and affordable solutions”, explained Roli Mathur, Head, Bioethics Unit, Indian Council of Medical Research (ICMR) over mail.

For many people living with the disease accessing even hydroxyurea, a medicine used as a first-line therapy for SCD, is a challenge in India. While researchers are doing their best to find a cost-effective treatment, there are chances of it still being beyond reach for most of them. “When you have such a blockbuster therapy, you also have to think about how you can make it accessible and many people around the world including us are working along those lines”, said Debojyoti Chakraborty, Principal Scientist at CSIR Institute of Genomics and Integrative Biology (IGIB).

The tribal population which is affected the most has limited healthcare access for various reasons: one being that they live in remote areas where there is a scarcity of healthcare professionals. “There is a need to provide primary care to deal with this debilitating disease that the community is suffering from. If you don’t do primary care then how are you going to do tertiary care?” asked Amar Jesani, a medical doctor, independent researcher, and teacher of bioethics and public health.

The Sickle Cell Anemia Elimination Mission launched in India on 1^st July 2023 aims to strengthen the existing healthcare system and improve primary, secondary, and tertiary healthcare teams. “Equitability is a factor which has to be accessed both at the local and global level. The government has a lot of power and we have seen how they can actually make things accessible to everyone like they did for vaccines. A similar modality would have to be put into place where you have partners from scientists, governments, and industries come together to see how you can get these kinds of therapies out”, said Dr. Chakraborty.

Indian regulation

The decision-making process for CRISPR research is governed by the existing legal and regulatory framework. The New Drugs and Clinical Trials Rules (2019) classify Gene Therapy Products (GTPs), including those developed through CRISPR, as new drugs, subjecting them to a thorough approval process by the Central Drugs Standard Control Organization (CDSCO). Additional requirements will be determined following the ICMR-DBT National guidelines for GTPs and oversight by bodies such as the Review Committee on Genetic Manipulation (RCGM) and the Genetic Engineering Approval Committee (GEAC) as applicable. Moreover, all biomedical and health research in India must adhere to the ICMR National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017.

Germline editing and CRISPR

Apart from the health equity and disparities associated with CRISPR, one of the biggest controversies has been about germline editing. Most of the scientific community supports the use of CRISPR to treat monogenic diseases. Germline editing is heritable and more complex and begs the question if it is even moral to subject an individual to heritable changes, even if it is to treat debilitating genetic conditions.

As of now, genome editing is restricted to somatic cells and there is a moratorium on germline editing. But when the advantages surpass the drawbacks, where will science draw the line with genome editing?

Chinese scientist He Jiankui took the scientific world by storm when he announced that he had edited healthy embryos in an attempt to minimise girls’ predisposition to HIV infection. This was in 2018 despite having guidelines against germline editing and at a time when studies had no clear-cut answers to the outcome of such an intervention. We still fully do not understand the long-term effects of CRISPR editing.

“It’s not a technology which is absolutely 100% full-fledgedly understood. [Germline editing] can come slowly, progressively once we have totally understood the pros and cons of the gene editing technology”, explained Dr. Chakraborty.

Guidelines, laws, and dialogues around ethical, societal, and safety issues need to evolve parallelly as technology evolves. “Most countries including India have forbidden genome editing in human embryos through legal instruments or through guidelines. In India every Institution involved in biomedical research is required to follow ICMR National Ethical Guidelines and register with the ethics committee which monitors research (including around gene editing)”, said Dr. Mathur.

The gene editing technology has also raised concerns regarding it becoming a commodity that wealthy parents will exploit to improve the fate of their children not only for therapeutic purposes but for genetic enhancement. “There is a chance that if we do not have a way to distribute these therapies to different parts of the world where it is needed through whatever mechanism, then you would have a division in the world because the therapy is there but the affordability isn’t there”, Dr. Chakraborty added.

Public engagement

Also given our incomplete knowledge about the long-term effects of CRISPR, researchers and policy-makers are considering real-world implications in the long run. The method is here to stay and the media and public need to engage in open dialogues to prevent the spread of misinformation. “Institutions undertaking cutting-edge research must also come up with best practices in community engagement, education, and timely and truthful communication to build trust among all stakeholders with a special focus on communities”, according to Dr. Mathur.

Written in an era before DNA was discovered, Frankenstein became an inspiration for science fiction and was one of the first novels to question the outcome of interfering with nature. It served as a reminder for scientists to proceed with caution and explore the moral consequences of scientific innovation. We have come a long way since then. Unlike the scientist in the novel, scientists today are aware of the power they hold with a technology that can change the genetic code and the societal implications for it, while also holding accountability for violating guidelines as seen in 2018.

At the end of the day, CRISPR is a tool whose endgame is determined by how humans utilise it. “Unless ethics is at the fore, even if there is scientific success, societal acceptance cannot be guaranteed. There needs to be enough commitment to integrate ethics in research work for the technology to have a positive impact”, explained Dr. Mathur.

(The author is a freelance content provider based in Hyderabad. )