On the Nature feature about the Sarafs, a rare disease, and time

Heidi Ledford has a tragic and powerful story published yesterday in Nature, about a team of scientists at the CSIR-Institute of Genomics and Integrative Biology racing to develop a CRISPR treatment for Uditi Saraf, a young girl whose brain was losing neurons due to a very rare, very aggressive genetic condition called FENIB. The story’s power comes from what it reveals about several facets of developing new treatments, looking for a cure for a rare disease, the importance of state support as well as control, the fact of the existence of neglected diseases, the demands made of clinical researchers, self-sufficiency in laboratory research infrastructure, and of course the cost of treatment. Most of all, it is a critical study of time. Uditi passed away four months after one of the researchers working on a CRISPR-based treatment for her told her parents they’d be ready with a solution for her in six. But even before her passing, there was time, there was no time, there was hurry, and there were risks.

Uditi’s disease was caused by a mutation that converts a single DNA base from a ‘G’ to an ‘A’. A variation on CRISPR genome editing, called base editing, could theoretically correct exactly this kind of mutation (see ‘Precision gene repair’). … But Rajeev and Sonam saw an opportunity for hope: perhaps such a therapy could slow down the progression of Uditi’s disease, buying time for scientists to develop another treatment that could repair the damage that had been done. The Sarafs were on board.

There were a lot of unknowns in the base-editing project. And in addition to the work on stem cells in the lab, the team would need to do further experiments to determine which base-editing systems would work best, where and how to deliver its components into the body, and whether the process generated any unwanted changes to the DNA sequence. They would need to do experiments in mice to test the safety and efficacy of the treatment. They also needed to get Ghosh’s facility approved by India’s regulators for producing the base-editing components.

Then there was the pandemic:

In December 2019, the Sarafs moved back to India. … Then the COVID-19 pandemic struck, and in January 2021, Uditi was hospitalized with severe COVID-19. She spent 20 days in the hospital and her health was never the same, says Sonam. Communication became increasingly difficult for Uditi and she began to pace the house incessantly, rarely even going to sleep. The Sarafs decided to speed up the base-editing project by funding a second team in India.

Developing treatments take time. Uditi’s story was a one-off, a singular disease that few researchers on the planet were working on, so developing an experimental alternative based on cutting-edge medical technology was a reasonable option. And yet:

Meanwhile, Devinsky had petitioned a US foundation to devise a different experimental treatment called antisense therapy for Uditi. … The treatments didn’t work. And the experience taught Rajeev and Sonam how long it could take to get approval to try an experimental therapy in the United States. They decided Uditi’s base-editing therapy should also be manufactured and administered in India.

Uditi didn’t live long enough to receive treatment that could have slowed FENIB’s progression — hopefully long enough for researchers to come up with a better and more long-lasting solution. Now, after her death, the thinking and effort that motivated the quest to find her a cure is in the future tense.

It will take years to establish the techniques needed to create rapid, on-demand, bespoke CRISPR therapies. Most people with these conditions don’t have that kind of time. … Rajeev has urged Chakraborty to finish the team’s studies in mice, so that the next person with FENIB will not have to wait as long for a potential treatment. … “We are not really trying as aggressively as we did earlier,” he says.

When the health of a loved one is rapidly deteriorating, the clock of life resets — from the familiar 24-hour rhythms of daily life to days that start and end to the beats of more morbid milestones: a doctor’s visit, a diagnostic test result, the effects of a drug kicking in, the chance discovery of a new symptom, an unexpected moment of joy, the unbearable agony of helplessness. The passage of time becomes distorted, sometimes slow, sometimes too fast. People do what they can when they can. They will take all their chances. Which means the chances they encounter on their way matters. Technological literacy and personal wealth expand this menu of options. The Sarafs knew about CRISPR, had a vague idea of how it worked, and could afford it, so they pursued it. They came really close; their efforts may even prove decisive in pushing a cure for FENIB past the finish line. For those who don’t know about CRISPR-based therapies and/or don’t have the means to pay for it, the gap between hope and cure is likely to be more vast, and more dispiriting. And one chapter of the Sarafs’ journey briefly threatened to pull them to this path — and relentlessly threatens to waylay many families’ laborious pursuits to save the lives of their loved one:

The Sarafs studied what they could find online and tried the interventions available to them: Indian ayurvedic treatments, a ketogenic diet, special schools, seeing a slew of physicians and trying out various medicines.

Ledford’s narrative doesn’t get into who these physicians were, but let’s set them and the special schools aside. Just this morning, I read a report by Rema Nagarajan in The Times of India that a company called Natelco in Bengaluru has been selling human milk even though its license was cancelled two years ago. The FSSAI cancelled Natelco’s license in 2021; a few months later, Natelco obtained a license from the Ministry of AYUSH claiming it was selling “Aryuevdic proprietary medicine”. When the Breastfeeding Promotion Network of India complained to the ministry, the ministry cancelled its license in August 2022. Then, a month later, the Karnataka high court granted an interim stay on this cancellation but said the respondents — AYUSH representatives in Karnataka, in the Karnataka licensing authority or from the ministry — could have it vacated. They didn’t bother. In June 2023, the ministry filed objections but nothing more. It finally moved to vacate the stay only in March this year.

Natelco’s case is just one example. There are hundreds of companies whose charade the Ministry of AYUSH facilitates by allowing specious claims ranging from “Ayurvedic toothpaste” to calling human breast milk “Ayurvedic medicine”. This is not Ayurveda: very few of us know what Ayurveda is or looks like; even Ayurveda itself doesn’t belong in modern medicine. But together with the FSSAI, the food regulation body notorious for dragging its feet when the time comes to punish errant manufacturers, and a toothless advertisement monitoring regime, the Indian food and beverages market has provided a hospitable work environment for quacks and their businesses. And inevitably, their quackery spills over into the path of an unsuspecting yet desperate father or mother looking for something, anything, that will help their child. When faced with trenchant criticism, many of these business adopt the line that their products are not unsafe. But they are terribly unsafe: they steal time to do nothing with it, taking it away from a therapy or a drug that could have done a lot. Such cynical alternatives shouldn’t be present anywhere on any family’s path, yet the national government itself gives them a license to be.