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The democratization of genomics and the mission to have no disease orphan by 2030 

"The history of genetics begins, not with Gregor Mendel’s pea experiments, but with people long ago noticing family resemblances and vulnerabilities so distinctive that shared environment alone couldn’t explain them.”   - Ricki Lewis 2023


Fiction and Facts: The physician-writer Dr. Abraham Verghese has written a magical and highly acclaimed work of fiction, “The Covenant of Water,” which is a multi-generational story of a Syrian Christian family in the South Indian state of Kerala from the early 1900s through eight decades. That Dr. Verghese wove this rich descriptive story around the central theme of a rare genetic trait is insightful of the challenges of India’s genomic health. A consequence of the practices of endogamy and even consanguinity in communities for generations and sometimes spanning centuries that one or the other such rare disease traits are a feature (sometimes called founder mutations) of many communities of India, including the Syrian Christians of Travancore. Throughout his fictional work, Dr. Verghese refers to the trait as “the condition.”


Fiction soon turned into fact, when the investigative journalist Chetana Belagere at South First came out in July 2023 with a three-part series of articles about the condition of Xeroderma Pigmentosum (XP) a rare condition that causes children to have extreme sensitivity to sunlight. A 2014 publication had already noted that “To date, 37 unrelated families with patients having XP have been reported from India. Many families have been reported from South India especially Karnataka, where significant consanguinity is observed.” The stories in South First bring the observations made in the publication to stark reality by describing in some detail the plight of several children in three villages in the Chamarajanagar rural district near the city of Mysuru who are kept indoors so their lifespans are extended into their teens. This “Covenant of Light” is now a fact in these families of modern Karnataka as noted by Dr. Deepa Bhat, Genetic Counsellor of JSS Medical College and Hospital in Mysuru who has spent time visiting and counselling these families. The geneticist Dr. Deepa Bhat and her colleague the dermatologist Dr. Dr Srishti Betsurmath point out that affected families are not willing to accept that consanguinity within the Banajiga Shetty community is a root cause of the higher occurrence of the XP condition. Dr Bhat emphasises the importance of genetic counselling for families with a history of XP, since it will enable them to better understand the risk of passing the condition down to their children.


A group of us become aware of these challenges in rare genetic diseases in 2013 when we had built, at India’s pioneering genomics company, Strand Life Sciences. Strand was the earliest clinical grade (CAP accredited) genome sequencing laboratories using NGS (next generation sequencing) in South Asia. We began routinely resolving diagnostic odysseys that many families were grappling with. In 2014, along with patient driven organizations and the Indian Association of Medical Genetics, we launched a national campaign for rare and orphan diseases at the Press Club of India behind Parliament House in Delhi and with some fits and starts, stumbling and substantial judicial activism we finally got to a national policy by 2021. The judicial activism was driven by tragic narratives of families denied medical attention, denied insurance coverage and collective lawsuits invoking the “right to life” directive principles of the Constitution of India. It is a matter of disappointment that India has still not recognised the right to health as a fundamental right through constitutional amendments and genuine reform. Vikas Bharat will need a healthy population in addition to demographic dividends.


The well-known population genetics scholar Prof David Reich, whose extensive collaboration with Professor Lalji Singh, Thangaraj Kumaraswamy and their colleagues from CCMB and CDFD in Hyderabad, notes that the incidence of serious genetic traits in the South Asian populations he has studied is far higher than that seen in even the Ashkenazi Jewish communities as a likely consequence of the prolonged practices of endogamy and consanguinity in our populations. These insights came from decades of research using cutting edge technologies in genetic analysis and statistical data analytics when these were out of reach of academia in India and required international collaborations to take forward.





This has changed dramatically now as the democratization of genomics is almost ubiquitous in many LMICs and India has been aggressive in building the necessary infrastructure and human capital to be a front runner. The pandemic was a trigger for India to invest heavily in capacity for diagnostics and genome sequencing and consequently the country is able to build some serious digital public infrastructure to understand the genetic diversity of India, indeed of all of South Asia, with extraordinary precision. Illumina installations in India alone have an NGS capacity of 32 peta-bases per run which translates to an ability to sequence 300,000 whole genomes per year.

Celebrating Moore’s law entering the second half of the chess board, Deep Learning began taking shape around 2006, as did initiatives like the Aadhaar project in India The idea that digital public goods can trigger social change became evident.


Commercialization and scale have dropped costs in information and communications technologies to create a “Telecom Hungama” in India where in less than two decades we moved from the world’s highest costs for data plans to the most affordable. The mobile revolution has now enabled the national unique ID project and its application in direct benefits transfers and financial inclusion emergent realities in the world’s most populous country.


Comparable to the exponential Moore’s Law in information processing, we have Flatley’s law of genomics that is racing towards the singularity tipping point measured as exponential reduction in cost. The genomics revolution dropping the costs of sequencing genomes (DNA) rapidly from 1Million USD per gigabase of nucleic acids is now approaching one dollar in just 20 years. Naturally, India has seen a frenzy on investments towards a Genomics Hungama. Today, you can get a whole exome sequence analyzed at a depth of 120X with genetic counselling by an CAP accredited lab for under 15,000 INR which is perhaps already the world’s most affordable genomic health insights test. The target would be to get it to a third of this cost to see the effects of the democratization of genomics.


It will not be long before the Ayushman Bharat Digital Mission (ABDM) will be India’s health stack with the ABHA ID as the health card that links health records with digital lockers for most citizens. Genomic data will need special handling both because of the size of raw genomic data, the sensitivity of this data and legal privacy issues. India needs a leapfrog in its healthcare regulation. Hospitals, doctors and labs need to be better regulated. Both in private and public health systems, self-regulation has had suboptimal results. At the same time, extensive regulations without the tools that make enforcement of the regulation feasible, do not make for effective safeguards. One way to make this leapfrog happen is to enlist technology for smarter regulation.

   

Genomic Health Insights: Solving diagnostic odysseys of patients with genetic disorders has been a challenge the world over with odysseys sometimes running for years or mostly never getting resolved. The genomics revolution has now begun to make a dent on this challenge in India. Some ten years back, a clinical specialist treating a child or an adult with a disorder that refuses to reveal itself would suggest sending the patient sample to a leading academic lab in the West at a Mayo Clinic or a Dana Farber to get some resolution often at enormous cost. Today, the option to send off to a lab in Bangalore, Hyderabad or Pune is often the advice at a far more affordable cost. Unfortunately, these options are still only open to a small fraction of those who need it and this simply does not have to be if there is an alignment of incentives that suggest that early resolution and precision diagnosis can lead to enormous savings of disability-adjusted life years of tens of millions of affected and their caregivers. The intent of this editorial note is to get us to wake up to challenging these misalignments.


Despite these challenges in public health systems, the empirical evidence of geneticists and treating physicians  is starting to build in support of the intuition that scholars like David Reich have pointed to i.e., India has genomic health challenges that need serious attention. The democratization of genomics has now opened the possibility of getting genomic health insights from sequencing healthy cohorts. Health and wellness mandates of many organizations and self-actualized citizens lead them to seek genomic tests to understand their health risks and adapt to them. What we present below is based on 100s of samples – which soon will be in 1000s and we should see these numbers hold up with more statistical rigour. 


Here are some highlights.

·       Over 70% seem to have useful pharmacogenomic insights on important medications. For example, a majority of those studied do not respond to Clopidogreal (Plavix). Several CNS medications also seem to need titration based on genetic factors.

·       Also, 40% of those sequenced have insights on health risks that they can act on. These include risks from carrier mutations that could affect progeny, hereditary cancer, cardiovascular genetic factors and genetic factors in metabolic disorders.

·       Over a third of the population studied have a genetic recessive carrier risk. The ones we see most often are beta-thalassemia, ataxia telangiectasia, cystic fibrosis and spinal muscular atrophy (SMA). The author found that he is a carrier of SMA as he is missing one copy of SMN1 gene. Such copy number variants can only discovered by deep sequencing which is now accessible.

·       Only a small fraction of cancer cases occur because of hereditary risk but when they do, the cancer can be more aggressive and occurs at an earlier age. Any family history of cancer needs to be noted in a risk calculator by trained genetic counsellors for advising family members. BRCA mutations causing breast and ovarian cancers in women and colorectal cancer in men are often discussed but actually close to 100 genes are associated with well-known hereditary cancer risks.

·       The incidence of cardiovascular disease in South Asian families have been noted in communities based overseas for example in the San Francisco Bay area with programs initiated at El Camino Hospital and taken up by the Kaiser Permanente health system and others for monitoring South Asian patients more closely for heart health and wellness. Being aware of hereditary genetic risks in genes KCNQ1, NEXN, DSC2 and APOB would provide alerts for closer monitoring and attention to lifestyle changes for better heart health. 


It is important to understand that the analysis presented above are indicative of the trends but as the coverage increases and the statistical estimates get more robust there may be some variation. But the highlights and the message is clear. The world’s most populous nation is facing serious health risks due to its genomic traits and social practices of endogamy. This has become clear to the health authorities and discussion of rare and orphan disease challenges are now often in public media with human interest stories of specific cases. There are special annual rare disease days for different disorders, social media campaigns and occasional striking judicial appeals and rulings in the higher courts.


The national policy for rare diseases (NPRD) instituted by the Government of India in 2021 set us on a path to build the first national registry of orphan diseases at ICMR and various research programs were initiated at the DBT and ICMR to support centres of excellence (COE) for orphan and rare genetic diseases. This conceptualization of the NPRD and its impact on the rollout of national priorities for action through the COEs were to be buffeted by the recently appointed UMMID committee (DBT initiated unique methods and management of treatment of inherited disorders) to work on training of medical personnel on genetics, NIDAN Kendras for diagnostics and focussed effort on aspirational districts for preventive action. These are important first steps towards developing genome based precision medicine in India and taking forward the mission of no disease orphan by 2030.


Registry: Evaluating Disease Burden and Digital Public Infrastructure: While policies are an important statement of intent to direct public agencies and resources towards addressing important unmet needs of a large segment of the citizenry. Just how large is largely a matter of guesswork and various stakeholders have held out that somewhere between 50 Million and 100 Million Indians are affected by these orphaned and rare genetic disorders. Orphaned because either public health agencies deem them rare and therefore low in priority for a nation beset by many health crises, or orphaned simply because commercial pharmaceutical industry and private healthcare providers do not seea market fit for products and services within their capacity to provide. The payer sector (insurance both public and private) would be responsive once the pharma and providers are active and the actuarial calculations suggest that genuine value can be delivered.


None of this can move forward until a national orphan diseases registry can be realized. The national policy has entrusted the Indian Council of Medical Research with building this registry.  As we will see below, the advances in AI based screening, populational scale digital health systems (ABDM), genomics-based diagnostics and agent based synthetic population simulation models can accelerate this core activity. But this would require a truly multi-disciplinary team effort that the nation showed such ability to bring together in response to the pandemic on a wartime footing. A Vikas Bharat with no disease orphan requires a peacetime response of equal vigour. Can Co-WIN be adapted to become the national registry for orphan diseases?


The DBT (Department of BioTechnology, Government of India) has undertaken a bold experiment to build the Genome India database of 10,000 whole genomes as a public digital infrastructure . The Genome India project is a multi-institutional project anchored at the Centre for Brain Research (IISc), CCMB, IGIB and NIBMG. The publication on the major findings will be out by late summer and the DBT has announced that the data will be made a public good through the IBDC facility in the national capital region (NCR) to empower research and innovation on the genomics in India. The details were shared with the nation in February of 2024.


The goals and impact of Genome India are to create an exhaustive catalogue of genetic variations in Indians and a reference haplotype for Indians by carrying out whole genome sequencing of 10000 samples from 100+ communities. Design genome-wide and disease-specific genetic panels for low cost  diagnostics and research. While the original intent was to create gene chips also called microarray panels, but the speed at which sequencing based technologies are becoming affordable, a forward looking policy may be to focus on sequencing panels to drive screening and diagnosis. A core idea behind the Genome India project has to be to develop a biobank of 20000 blood samples for omics research to be localized. The UK driven Biobank has been an effective platform for the West and we need our own repository for all the reasons of the genetic diversity and specificity of founder mutations in South Asians.


The power of digital public infrastructure at a billion scale has launched India into a leadership role globally with the effective national ID project, unified payment interfaces and financial inclusion which was clearly the banner that was flown throughout India’s G20 campaign in the last couple of years. For the West, the internet, the NCBI and EBI data repositories, the UK Biobank and the All of US precision medicine initiatives have been seen as the DPIs that have launched and continue to drive the science and  technology innovation leadership of the West in the life and health sciences.  If we want India to repeat the success of the financial technology sector in biotechnology, we need to seriously consider making genomic data from Genome India available for public access for research purposes (via IBDC) and make it the paradigm shift that would allow us to stand tall.


A genuine obstacle for the registry to be effective is the issue of privacy of health data and the enormous risks of discrimination that an identified affected individual and their family and community faces can be a huge disincentive for compliance. Many clever “techno legal” fixes are possible but will need the power of law for enforcement. Western societies have enacted one form or the other of what the USA (GINA 2008) calls the genetic information non-discrimination act to protect citizens from discrimination in employment and health insurance and other services resulting from genetic information. While India has enacted a data protection law DPDPA in 2023, we would do well to also pass a GINA type law as an act of parliament without which the genomic revolution will remain only of academic interest.


Social Awareness: Prevention: In addition to the core national registry of rare disease patients, we will need a social awareness campaign at the scale that we have seen the tobacco eradication campaigns now active across the country having impact. The causal link to lung as well as head and neck cancers have made the campaign effective. We could of course make similar communication content that links risk of serious genetic disorders with continued practices of endogamy and  consanguinity. However, since this social behaviour is deeply rooted in cultural and community norms, a more effective strategy would be to encourage counselling, screening and consideration of IVF and prenatal testing in high-risk situations.


A few days before, after the marriage broker had come and gone, she overheard her uncle chastise her mother, saying, “So what if his aunt drowned? Is that the same as a family history of lunacy? Whoever heard of a family with a history of drownings? Others are always jealous of a good match and they’ll find one thing to exaggerate.”  This early passage from the Covenant of Water is very telling of the problem of social stigma that has kept medical science in genetics (the drownings caused by autosomal dominant trait of NeuroFibromatosis Type 2 (NF2) and consequent acoustic neuromas) from playing a larger role in taking a scientific approach to preventive strategies in India. Other nations such as Cypress, Israel, or now some Middle Eastern countries which are hot spots of Tay Sachs or Thalassemia have taken proactive approaches to screening and counselling that we can learn from.


Since every 25th Indian seems to be a carrier of Beta-Thalassemia – we could expect around 10,000 babies a year born a Thalassemia major.  India is now intending to screen every pregnant woman for carrier status in major initiatives at Government hospitals. The burden of disease has now triggered action and screening and prevention of sickle cell and thalassemia are now a priority in several states. There could be social consequences of carrier status becoming public and will need careful handling of privacy and counselling of families. FOGSI (Federation of Obstetric and Gynaecological Societies of India) has a large responsibility to see this through.


This vignette storyboard on Beta-Thalassemia awareness was created by Dr Namitha A Kumar for the World Thalassemia Day and rendered as this video by Itihaas Interactive.



Some effective social communication is required for better compliance and voluntary participation. Effective digital intervention could play an important role in creating scientific awareness and gradually chip away at the social stigmas of genetic traits and awareness that early detection and preventive healthcare interventions can manage many of these genomic quirks that we carry. Digital (mobile) games introducing genetics and the genetic health insights are effective ways of educating young people and making them aware of some of the risks associated with carrier genetic biomarkers that so many of us are affected by.  Storyboards turned into vignettes and graphic novels and voice and video delivered content using AI to localize and deliver in local dialects should be very possible with the tremendous progress being made through the Bhaasha and Vaani initiatives. These will gradually chip away at the stigmas that our society still carries.  


Innovation in Therapeutics for Orphan Diseases: The Orphan Drug Act in the USA was shepherded by these biotechnology pioneers who saw the with the right economic incentives, business models could be created for these promising therapies to both help the patients and build great companies. Fast tracking through regulatory and some exclusivity provisions were the hallmarks as incentives that propelled the creation of early orphan drugs. Liberal reimbursements by payors eventually has given biopharma in the west a substantive new market opportunity in innovation of therapeutics for orphan indications.  Some thirty years later, ABLE (the apex industry body for biotechnology in India) similarly shepherded early provisions of orphan drug incentives with regulatory agencies at the office of the Drug Controller General of India (DCGI).


For a large class of lysosomal storage disorders (LSDs) the treatment for rare disease patients using enzyme replacement therapies (ERTs) is now a 40 year old strategy that Novozyme and  Genzyme (now Sanofi) pioneered in USA and Europe. These should have been a major focus of our biopharma atma nirbhar (self-reliance) with India’s capacity for biologicals and protein engineering.  The misalignments as to why this hasn’t happened must be identified and corrected. The protein science and engineering capabilities in the country have been focussed on biologics manufacturing for clinical (largely for oncology and metabolic disorders) and industrial products. We do need to create centres of excellence around protein science to be able to navigate intellectual property hurdles in therapeutics for orphan indication. Most important, there have to be procurement guarantees of various kinds to ensure some derisking for the companies that are willing to step forward.


The Indian Council of Medical Research (ICMR) initiated the first n-of-one trial of an ASO (anti-sense oligotherapy) “first in the world” treatment for exon splicing in a young boy with a frameshift mutation in the dystrophin gene which had manifested as Duchenne Muscular Dystrophy (DMD). The research and development for making the medicine was pioneered by the Dystrophy Annihilation Research Trust (DART), a heart wrenching story of extraordinary measures taken by the parents of children (boys) affected by DMD by throwing their life mission into creating medicine to save their children. It is believed that around one in thirty-five hundred male births results in a DMD afflicted child. In India this would mean a disease burden of around fifty to one hundred thousand affected. Imported medicine which only works for a handful of mutations like Exondys 51 cost Rupees 2-3 Crores for a small child’s dose. The same US based company has now a gene therapy in the market approved by FDA for a 3.2Million USD reimbursement. DART is undertaking a clinical trial with over 50 patients across India at a cost of USD 25,000 per patient per year.


Cell and Gene therapy for these genetic disorders seems imminent with clinical studies starting up globally and indigenously. Cell therapies have received a major focus in research and development. Stem cell therapies were the first focus and Stempeutics was perhaps the first company in India to receive regulatory approval. Immunoact and Immuneel are two companies in India that have been approved to sell chimeric antigenic receptor T-cell therapy (CAR-T) now for patients in India at 5-10% of the equivalent treatment in the West. While these cell therapies do not address orphan genetic disorders directly, the infrastructure and delivery technologies (viral and non-viral vectors) are the building blocks we will need control of to move towards curative gene therapies.  

 

The recent breakthroughs in India with gene therapies for haemophilia (with ongoing clinical trials at the Centre for Stem Cell Research (CSCR) at CMC Vellore) and hemoglobinopathies are noteworthy. India is in the pre-clinical stage of developing gene-editing therapies for sickle cell disease (SCD) using CRISPR technology at CSCR in Vellore and at the Institute of Genomics and Integrative Biology (IGIB). It is a matter of pride that Dr Chakraborty (IGIB) and CSIR in India have been granted USPTO patent (11,970,699 B2) on April 30th 2024 for kinetically enhanced and engineered FnCas9 and its uses thereof. India now has some clear white space in the CRISPR IP landscape. Sensing that India would soon embark on development of these therapies for genetic disorders, guidelines were initiated in 2017 by the the Director General ICMR (Indian Council of Medical Research), a physician scientist, Dr Soumya Swaminathan

The story of DART is poignantly told by the podcaster Rahul Matthan in the ExMachina episode on The Incurable Disease. The similar story of John Crowley who helped create enzyme replacement therapy for his children affected by Pompe Disease an LSD was documented as The Cure by the Wall Street Journal reporter Geeta Anand and won her a Pulitzer Prize. A recent article in Nature News Feature by Heidi Lederman describes the story of a young woman afflicted by a rare neurodegenerative disorder and the race by the Chakraborty Lab at IGIB and Grow Labs to save her. The scientists came close to getting past pre-clinical stage but could not save the young woman. As Lederman says, “it will take years to establish the techniques needed to create rapid, on-demand, bespoke CRISPR therapies.”


Some thirty plus gene therapies have been approved globally including the first CRISPR gene editing based therapy for Sickle Cell Disease in 2023 by Vertex Pharmaceuticals in partnership with CRISPR Therapeutics. The cost will be USD 2.2 Million for the treatment and will also require exye=tended hospitalization. Dr Fydor Urnov is the chief medical officer of the Innovative Genomics Institute set up by Professor Jennifer Doudna, the Nobel prize winning chemist and inventor of CRISPR-Cas9 gene-editing. In an emotional guest essay in 2022 in the New York Times, Dr Urnov says, “The invention of CRISPR gene editing gave us remarkable treatment powers, yet no one should do a victory lap … We must, and we can build a world with CRISPR for all.” Perhaps a Viksit Bharat with no disease orphan is an option that we must make possible.




Acknowledgements: The author would like to thank the LMSAI for the invitation to give this talk at the Annual Cambridge Symposium on South Asia. Also a special thanks to Professor David E Bloom, his host at HSPH. The Master Plan for No Disease Orphan 2030 emerged from the guest lecture to the class on global population and health in September 2023.


REFERENCES

 

[1] Ricki Lewis,” The Covenant of Water by Abraham Verghese: A Geneticist’s Review,”  PLOS Blogs, DNA Science, Aug 2023.

 

 

[3] Tamhankar PM, Iyer SV, Ravindran S, Gupta N, Kabra M, Nayak C, Kura M, Sanghavi S, Joshi R, Chennuri VS, Khopkar U. Clinical profile and mutation analysis of xeroderma pigmentosum in Indian patients. Indian J Dermatol Venereol Leprol. 2015 Jan-Feb;81(1):16-22. doi: 10.4103/0378-6323.148559. PMID: 25566891.

 

[4] Rajasimha HK, Shirol PB, Ramamoorthy P, Hegde M, Barde S, Chandru V, Verma IC. Et al., Organization for rare diseases India (ORDI) - addressing the challenges and opportunities for the Indian rare diseases' community. Genet Res (Camb). 2014 Aug 13.

 

[4] https://www.c-help.org/post/the-right-to-health-a-position-paper (A position paper on the Right to Health as a Fundamental Right in India).


 

[Vijay Chandru leads the No Disease Orphan 2030 Mission at the Centre for Health, Education and Technology at IIACD in Bangalore. He Co-Founded Strand Life Sciences and CrisprBits and serves on the faculty of the Centre for Brain Research at Indian Institute of Science. He is a visiting scientist/professor at Harvard School of Public Health, National Centre for Biological Sciences and the Koita Centre for Digital Health at Ashoka University. The views expressed here are personal and unrepresentative of his institutional affiliations. He can be reached at chandru@alum.mit.edu ]

 

 

 

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