In places like Saharanpur and Buldhana, a rare genetic disease has been taking away control of bodies, lives and livelihoods from entire neighbourhoods. Against all odds, a few scientists and doctors are determined to ease the pain.
When I met Mohammed Faruq in August 2021, he was still grappling with a problem he’d been working on since 2006. Faruq was 41 years old now, his shoulder-length hair salt-and-pepper. We were in a laboratory on the sixth floor of the Institute of Genomics and Integrative Biology in Delhi, where he was looking at colourful bands, long and short, on his computer screen. They’d been spat out by a software that processes DNA samples. Faruq analysed thousands of such samples over the years, he was telling me, when his phone rang.
The call was from Mohammad Aarif, who lives in Mau district of eastern Uttar Pradesh. Faruq took Aarif’s permission to put the call on speaker.
“Is there any progress?” asked Aarif.
“The research is going on,” Faruq replied, “but we are far from any solution.”
“I came to visit you in 2007,” Aarif said. “It’s been so many years since you’ve been researching. Why is nothing happening? I have started to curse Allah now. I have heard there is a fakir in Karachi who could help. I’m thinking maybe we should go there.”
Above his many-coloured screen, Faruq’s face was helpless.
Some weeks before meeting Faruq, I was in Saharanpur in western Uttar Pradesh, about a four-hour drive from Delhi. There, I visited a home in which three single beds were arranged in the shape of an inverted ‘U’. Mohammad Hamid, who is a little over 70, lay on the bed at the back. Niyamat Ilahi, his frail 68-year-old wife, lay to his right. Her eyes were fixed on the third bed, occupied by their 45-year-old son Mohammad Shahid.
Shahid, all bones and skin, grew restless as the day progressed. He kept tossing and turning, trying to find a comfortable position. His unsteady hands wrestled with the red pillow before giving up. Sometime after noon, I noticed Shahid moving his jaws, trying to form words. None came. Finally, he managed a sound that broke the silence of the room.
“Are you hungry?” His younger sister Rashida had rushed in. Shahid nodded before turning to face the wall again. This is how he had spent the last four years, in this bed.
Shahid, his two younger brothers, and Ilahi, like Faruq’s caller Mohammad Aarif, are living with spinocerebellar ataxia. It’s a rare neurodegenerative disorder that takes its name from the Greek for ‘lack of order,’ and causes people to gradually lose control over body movements. Walking, hailing a taxi, holding a cup of tea, writing, speaking, swallowing: these are the sort of simple everyday movements that ataxia patients often struggle with.
Eventually, many ataxia patients in resource-strapped countries like India end up spending their days in bed, dependent on others, until they die. People like Shahid remain invisible to the health system because they don’t have popular champions. Institutional support for ataxia is almost negligible. For decades, they’ve held on to one strand of hope: the work of a few determined doctors and scientists who’ve been trying to get to the bottom of this terrible mystery.
Base Repeats
But sometimes, gene mutations cause certain base sequences to repeat more often than they should. For instance, when a base repeat like CAGCAGCAGCAGCAG crosses a safe limit, it leads to the formation of abnormally long chains of proteins. The proteins accumulate in the brain and begin to damage the cerebellum, the butterfly-shaped part of the hindbrain. The consequences are drastic because the cerebellum controls all voluntary movements in humans.
In spinocerebellar ataxia, sequence repeats get longer in successive generations of patients. Longer repeats imply that the disease gets more severe, and symptoms appear sooner. In some cases, the symptoms make their presence felt as a person enters their teens. By the time they enter college, their movements become frustratingly slow and awkward. Some have dropped out due to shame. For communities living with SCA in India, the stigma is so pervasive that some patients, women in particular, stop leaving the house altogether.
SCA affects roughly three out of every 100,000 people in the world. As rare as that incidence seems, it’s still the most prevalent kind of hereditary ataxia we know of. Even though it affects thousands of people in India, it finds no mention in the government’s National Policy for Rare Diseases, primarily because India hasn’t arrived at a comprehensively acceptable definition of what a rare disease is. Globally, these definitions are derived from careful studies of populations. In India, the government blames the lack of enough data for not having arrived at a figure.
“I visited you in 2007. It’s been so many years since you’ve been researching it. Why is nothing happening?”
Together, rare diseases affect 350 million people worldwide, more than the entire population of the US. “That’s a lot of people,” said Anne Pariser, director of the Office of Rare Disease Research at the National Institutes of Health, US. “Rare diseases are really not, in fact, rare, when considered collectively.”
India’s policy currently covers only those rare diseases for which treatments are available, like cystic fibrosis and Fanconi anaemia. But only five percent of all 7000 or so rare diseases have treatments. For the others, including SCA, the national policy doesn’t commit any research funds.
Generations of families have been living with SCA in India. “No hope,” said Drupadabai Kshirsagar when I met her in Buldhana town in Maharashtra. Drupadabai, a woman with a stony face but moist eyes, had lost her husband and one daughter to SCA. Ashish, her 35-year-old son and Pushpa, her 45-year-old daughter, are living with the disease.
Ashish used to play state-level cricket in his youth, and Pushpa used to be a school inspector. The walls of the Kshirsagars’ house had iron handles at half metre intervals, which Pushpa used to move around. Ashish was in a wheelchair. Their 67-year-old mother was their only caregiver. “I worry what will happen to them after me,” Drupadabai said. “The only hope I have is from God.”
Early Tremors
Roughly a decade later, an American neurologist named Roger Rosenberg was on a hospital tour in India. Scientists were now beginning to classify certain movement disorders as ataxias, based on distinct clinical features, and Rosenberg was looking for patients living with Joseph Disease. It gets its name from Antone Joseph, in whose family it was first reported in Portugal. Rosenberg was visiting former Portuguese colonies on the assumption that the disease had been passed down to native populations.
When he showed up at the neurology department of the All India Institute of Medical Sciences in Delhi, the institute asked a young neurologist named Satish Jain to help him. Jain invited some patients who had the tremor symptoms Rosenberg was looking for.
Rosenberg identified two patients who seemed to have Joseph Disease. Later, Jain found more people with similar symptoms. “The fact that it followed a pattern was very interesting,” Jain told me. It became clear to him that this movement disorder existed in communities where endogamy was strictly followed. (Some of his early patients came from a Hindu trader community of western Uttar Pradesh. The people I met in Saharanpur were part of a Muslim community of traders believed to have migrated from Afghanistan. All the individuals in the story consented to be named, but I am not naming the groups because of privacy concerns. Elders worry that it will dim the marriage prospects of young people in the community.)
Meanwhile, through the 1980s and most of the 1990s, the way to learn more about ataxia was through autopsy or brain imaging tools like MRI. But then DNA sequencing completely changed the game. That story started in May 1985, when a telescope-building project at University of California, Santacruz, fell through. The university’s chancellor, Robert Sinsheimer, proposed an audacious alternative: why not use the $30 million grant to map the whole human genome with its billions of bases?
The proposal split the scientists listening down the middle. A mammoth initiative like this would leech resources from worthy but relatively smaller projects, the critics argued. But the US Department of Energy and the National Institutes of Health decided to back the idea. In 1990, they launched The Human Genome Project with $3 billion and a 15-year timeline. The bet paid off. Over time, the learnings from the project helped transform our understanding of the genetic origins of diseases.
By the time the project began, researchers working on movement disorders had figured that ataxias could be of several types. A single type, such as SCA, had its own subtypes. Scientists from across the world were reporting SCA subtypes in their countries, and were looking for the specific genes causing them. Gradually, interconnections began to emerge. Researchers in Cuba, for instance, found several families in Holguín province displaying the same characteristics that Noshir Wadia had described.
So far, 48 such subtypes have been discovered globally. Of them, SCA-3, which Rosenberg was tracing in former Portuguese colonies, is the most common. The second-most common is SCA-2, the subtype that many people in Holguín province and Saharanpur district are living with. It is still a mystery where this mutation originated and how it spread to or from regions as far flung as south-eastern Cuba and northern India.
The Genomics Project
The dependence on foreign labs irked Samir Brahmachari, a biophysicist at the Indian Institute of Science in Bengaluru. Brahmachari worked on repetitive DNA to understand its connection with diseases, and he was particularly annoyed by the fact that foreign scientists who used samples from India wouldn’t equitably share credits with Indian researchers in published studies. “There have been instances of exploitation and a scramble to collect DNA samples (from India),” he wrote in Nature in 1997.
In August 1997, he moved to Delhi to head the Centre for Biochemical Technology, which operated under the umbrella of the Council of Scientific and Industrial Research. With the help of a grant, Brahmachari set up a functional genomics centre in the CBT. It would become the first institution in India to advance research on ataxias. Gradually, the CBT’s focus shifted from biochemical to genomics research. (In 2002, the centre would be renamed the Institute of Genomics and Integrative Biology—IGIB).
Around the time Brahmachari was starting the genomics centre, he ran into Jain at a genetics conference in Amritsar. They decided to collaborate on ataxia research. Jain would examine patients at AIIMS and send blood samples over to the IGIB.
Brahmachari hired Mitali Mukerji, a young PhD researcher, to study ataxia and help develop a diagnostic test. “At that time, nobody knew what ataxias were prevalent in India,” Mukerji said. She is now a professor of bioengineering at the Indian Institute of Technology, Jodhpur. “Nobody knew how to test them. It was a blank slate.”
Mukerji developed the first iteration of the diagnostic test in the late 1990s. It enabled the tester to find the elongated sequence in the patient’s DNA and match it against a panel of standard repeat sequences of various types of SCAs.
In the early 2000s, Jain had begun to move away from ataxia research, not because he’d lost his fascination for the subject, but because of a career-related disappointment whose details he preferred not to disclose publicly. In 2002, he decided to leave AIIMS and focus his energies on epilepsy research.
But before he quit, he handed over the ataxia work to Achal Srivastava, his PhD student. Srivastava and Mukerji continued to collaborate, and patterns finally began to emerge. SCAs were widespread; SCA-2 was the most common type; there were community clusters of particular types of SCAs in specific geographies: SCA-3 in Buldhana, SCA-2 in Saharanpur, SCA-1 near Vellore, Tamil Nadu. (It didn’t come as a surprise to Mukerji that people from these communities almost never married out.)
All these communities have been vital to ataxia research in India. An old couple once welcomed Wadia to a family wedding in Madhya Pradesh so he could collect the blood samples of as many people as he wanted. A teacher in Buldhana collaborated with a local politician to invite AIIMS and IGIB researchers to examine the town’s patients. And it was Laique Ahmed, Shahid’s maternal uncle, who hired a car in 1999 and had ten members of his community driven down to AIIMS from Saharanpur.
Losing Balance
Rashid estimated that over 40 families from his community were living with SCA in Saharanpur. Members of about 25 of these agreed to give their blood samples to Sonakar. Many who refused to get tested preferred not to know whether they had SCA. Even Rashid’s family was split. Rashida, Shahid’s sister, didn’t give her blood samples. Neither did her two youngest brothers. “I didn’t have the courage,” Rashida told me.
“Ataxia is the worst feeling in the world. People die in accidents, get heart attacks. With ataxia, you die every day.” – Shakir
Rashida is the fourth of eight siblings. Two of the three older siblings—Shahid and Rashid—have been diagnosed with SCA. Of the four younger than her, only one, Shakir, got himself tested. He was positive. Shakir is 30 now. As he took me around Saharanpur on his motorbike, he said he could already feel his body slowing down. “Ataxia is the worst feeling in the world,” Shakir said. “People die in accidents, get heart attacks. With ataxia, you die every day.”
The awareness of the disease was crushing. Sometimes, he told me, he felt it might have been better not to get tested. He’d dissuade his younger brothers from getting tested in the future. “I don’t want them to feel what I feel,” he said.
Shakir had seen his elder brothers’ decline. Shahid “had so many friends, many more than any of us,” Shakir said. “He was the most handsome man in our group and loved to dress up,” Naved Ashraf, Shahid’s childhood friend, told me. “Ladkiyan marti thi uss pe.” The girls were gone on him. Shahid even auditioned for a short film that somebody was shooting near Saharanpur.
But those days were long past. Shahid had withdrawn himself from the world five years ago. While their mother, Ilahi, had dealt with the disease more stoically, he had taken it to heart. “Maybe he is not able to accept his condition,” Rashida said. “He is constantly fighting with himself.”
Shahid sometimes resented his dependence on others, Rashida felt. He’d tighten his body whenever his brothers took him to the bathroom. “The biggest frustration patients have is that they cannot express themselves,” Rashida said. “Neither through voice nor through gestures. And we can’t understand what they are trying to say, which frustrates them more.”
In many ataxia-hit households in Buldhana and Saharanpur, I saw old parents caring for their adult children, trying to instill hope, strength and a modicum of joy. Shahid’s father Mohammad Hamid, for instance, had a penchant for inspirational Urdu couplets.
Irade jinke pukhta ho,
Nazar jinki khuda par ho,
Talatum hez maujon se,
Woh ghabraya nahi karte
Those who are strong-willed and believe in God, they are not afraid of upheavals in life. Rashid, Hamid’s third born, also enjoys Urdu poetry. But the lines he recited to me were not upbeat like his father’s. While referring to the social isolation caused by the disease, he said: “Woh din hawa hue jab paseena gulab tha, ab itra bhi lagao toh mohabbat ki boo nahin.” There was a time when our sweat smelled of roses. Now, even after wearing attar, the fragrance of love is gone.
Rashid, almost 40, occupied the room adjacent to the one with the three single beds. He used to teach in a primary school in Saharanpur. He still remembers the day ten years earlier when he realised something was wrong with his body. He was walking on the street when somebody called his name. When he turned to look back, he lost his balance and almost fell.
In the following months, he started fumbling while buttoning up his shirts. In class, he had trouble writing on the blackboard and tripped over words that were easy to pronounce. During staff meetings, he felt that everyone was looking at him. “That made me feel disabled,” Rashid told me. “I felt that my worth was declining.” Eventually, Rashid quit his teaching job. Now, he can eat on his own but cannot walk without support.
Between caring for him, Shahid and Ilahi, Rashida said she was on her toes for most of the day. Her younger brothers ran the family’s confectionary shop in the city. Rashida did everything at home: cooking, cleaning, feeding the patients, bathing Ilahi and assisting her in the bathroom. She has decided to stay unmarried. “I am on autopilot and have no interest in life,” she told me. “What is it worth?”
Finding the Centre
Their youngest brother manages a family shop in Saharanpur. “He is very active in the shop,” the man told me. “We were worried that if he gets to know, he will slip into depression.” Your brother already has two children, I asked. What if he plans more? “Yes. That is there too.”
Almost all the families I met in Saharanpur and Buldhana said they needed supporting infrastructure close by: a testing facility, a care home, specialist counsellors. That sort of ecosystem will help patients and their families make informed decisions, including getting foetuses tested.
“The disease affects our movement so we cannot keep running to AIIMS. Is that so difficult to understand?” – Shivashankar Gore
“The disease affects our movement, so we cannot keep running to AIIMS. Is that so difficult to understand?” asked Shivashankar Gore, a teacher in Buldhana. By Gore’s last estimate from 2015, over 30 families of his community in and around Buldhana are living with SCA-3. In Sakli, a nearby village, many patients don’t even know the name of the disease, or whether it can be diagnosed. Some of them are in their twenties. In the absence of awareness, children of the patients continue to marry within their community and have their own children.
Cuba has already done what patients in Buldhana and Saharanpur have been asking for. Given the high prevalence of SCA-2 in Holguín, the Cuban government has set up a specialised ataxia research and rehabilitation centre in the province. The centre is focussed on improving quality of life. It offers services such as walkers, adaptive housing and prenatal testing. It is staffed by psychologists and neurologists, and also trains researchers who are working on ataxias.
But if a centre of this kind is established in India, it will also have to contend with the extreme social stigma that SCA patients and their families have to deal with. Shahid’s relative struggled to find a bride for years even though he tested negative. When he finally found one, the bride’s side called off the alliance. In July 2021, two weeks before his wedding date, somebody informed the bride’s people that a disabling disease ran in the groom’s family.
“I told them they could see my reports, but people don’t understand,” the relative said. He then reached out to an agent to help him find another woman. This time, he didn’t disclose the family condition before getting married.
On my first visit to the clinic in early 2020, I saw that all the chairs outside were occupied. Some patients sat on the floor. They had come from Delhi, nearby states like Rajasthan and even from as far as Manipur. The youngest patient was a 14-year-old boy.
Akhilesh Kumar Sonakar, the clinician scientist who had visited Saharanpur, examined them and drew family trees to understand how the disease was being passed on. Sonakar works with the clinic’s head Achal Srivastava, to whom Jain had handed over his research in 2001.
About half of the roughly 20 people who visit the clinic every Saturday are in their twenties or early thirties. Srivastava said that most of them have ataxia patients at home: they come to the clinic to find out if they have the disease. Their decisions about careers and relationships hinge on this crucial finding. (Pramod Kumar Pal, a neurologist from NIMHANS Bengaluru, told me about some women whose symptoms started appearing post-marriage. Their husbands had either abandoned them or chosen to marry again.)
From AIIMS, the patients’ blood samples are sent to Mohammed Faruq’s lab at the IGIB in north Delhi. Faruq was hired in 2006 to research at the intersection of Srivastava’s clinical work and Mukerji’s genomics work. The IGIB lab alone has tested about 9000 samples so far.
During one of our many meetings, Faruq, who now heads ataxia research at IGIB, told me about a project he’s been supervising: its goal is to figure out the underlying process by which a base sequence repeat in DNA eventually damages the cerebellum. But a serious funding crunch meant that he’d been having trouble advancing this project.
The Indian government spends less than 1 percent of its Gross Domestic Product on scientific research. (China, in comparison, spends 2.2 percent, and Japan 3.4 percent.) In this year’s budget, the government has slashed funds for science by about 4 percent from last year.
Additionally, the government pushes scientific institutes to focus on ‘applied’ research such as developing diagnostic tools for diseases. ‘Basic’ research, important for understanding the working of diseases at the cellular level, gets the short shrift in this approach. From data accessed under the Right To Information Act, I learnt that of the ₹32 crore received by the IGIB from the Council of Scientific and Industrial Research between 2015 and 2021, only 2.5 per cent (₹80.5 lakh) was deployed for targeted basic research.
Mice and Men
More recently, Faruq managed to make some headway with the ICMR. In late 2021, he received some funds to discover new SCAs in India. “This is helpful and we have travelled a good distance since the research started,” Faruq said. “But the funds we have are nowhere close to what we actually need to be able to make a difference in patients’ lives.”
Critically, funding influences how many researchers enter a scientific field. Although neurology is a hot research area, most researchers prefer to work on relatively common diseases such as Alzheimer’s and Parkinson’s. “That’s natural. Everyone wants to play cricket,” said Faruq. “How many are throwing a javelin?”
When Faruq evaluates research proposals as part of government committees, he almost never sees proposals on ataxias. Achal Srivastava told me that ataxia needs a champion in the government. “Even if we get one person,” he said, “that will be a game changer.”
Ataxia research is moving at a much faster clip in western countries. After lab research in mice showed positive results, researchers are planning to run phase 1 trials of an experimental treatment on SCA-1 and SCA-3 patients in Europe and the US. The trials are scheduled to take place later this year. “That work is the most exciting,” Andrea Németh, clinician scientist at the University of Oxford and a supervisor of some of the trials, told me. “It looks like the most tractable way to get a disease-modifying drug into clinical practice in the next few years.”
“I think it’s good to have the data in mice. But we know that all these mice experiments are not very predictive for human trials.” – Thomas Klockgether
But, as in all scientific research, uncertainty is not far behind the excitement. “Unfortunately, there is no confidence,” said Thomas Klockgether, director of clinical research at DZNE in Bonn, whose centre is participating in the SCA trials. “I think it’s good to have the data in mice. But we know that all these mice experiments are not very predictive for human trials.”
Even if clinical trials lead to therapies, they are unlikely to be accessible for patients in lower- and middle-income countries like India. Rare disease treatments tend to be obnoxiously expensive. The one-time gene therapy for spinal muscular atrophy, for instance, costs $2 million (approximately ₹15.2 crore.)
India’s rare disease policy unequivocally states that the government cannot afford to foot the full bill for these costly treatments. In August 2021, the health ministry launched a crowdfunding portal for patients to request donations for rare disease treatment. Until 8 March of this year, 239 patients had registered on the portal. Together, they had been able to raise only ₹115,866. “Not enough to treat even one child,” said Prasanna Shirol, executive director of the non-profit Organisation for Rare Diseases India.
Neither the Ministry of Health and Family Welfare nor the ICMR responded to several emails requesting an interview.
Rashida and Tabish started reciting the kalma, read ritually over a dying person. Shahid’s lips moved, as if he, too, were reciting the words.
Hamid, their father, asked Tabish to bring a flower. Tabish ran out and plucked a rose from a garden nearby. He placed it near Shahid’s nose. Not long after, Shahid took his last breath.
Niyamat Ilahi’s tears didn’t stop for days as she lay in her bed. Now, Rashid occupies the third single bed in that room.
Ankur Paliwalis an independent journalist who writes about science, inequity, and his LGBTQ+ community. He currently lives in New Delhi.
