Tag: CRISPR/Cas9

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.

Corrected: ‘Life’s Greatest Secret’ by Matthew Cobb

An earlier version of this post was published by mistake. This is the corrected version. Featured image credit: amazon.in

When you write a book like Siddhartha Mukherjee’s The Gene: An Intimate History, the chance of a half-success is high. You will likely only partly please your readers instead of succeeding or even failing completely. Why? Because the scope of your work will be your biggest enemy, and in besting this enemy, you will at various points be forced to find a fine balance between breadth and depth. I think the author was not just aware of this problem but embraced it: The Gene is a success for having been written. Over 490 pages, Mukherjee weaves together a social, political and technical history of the genome, and unravels how developments from each strain have fed into the others. The effect is for it to have become a popular choice among biology beginners but a persistent point of contention among geneticists and other researchers. However, that it has been impactful has been incontestable.

At the same time, the flipside of such a book on anything is its shadow, where anything less ambitious or even less charming can find itself languishing. This I think is what has become of Life’s Greatest Secret by Matthew Cobb. Cobb, a zoologist at the University of Manchester, traces the efforts of scientists through the twentieth century to uncover the secrets of DNA. To be sure, this is a journey many authors have retraced, but what Cobb does differently are broadly two things. First: he sticks to the participants and the progress of science, and doesn’t deviate from this narrative, which can be hard to keep interesting. Second: he combines his profession as a scientist and his education as an historian to stay aware, and keep the reader aware, of the anthropology of science.

On both counts – of making the science interesting while tasked with exploring an history that can become confusing – Cobb is assisted by the same force that acted in The Gene‘s favour. Mukherjee banked on the intrigues inherent in a field of study that has evolved to become extremely influential as well as controversial to get the reader in on the book’s premise; he didn’t have to spend too much effort convincing a reader why books like his are important. Similarly, Life’s Greatest Secret focuses on those efforts to explore the DNA that played second fiddle to the medicinal applications of genetics in The Gene but possess intrigues of their own. And because Cobb is a well-qualified scientist, he is familiar with the various disguises of hype and easily cuts through them – as well as teases out and highlights less well-known .

For example, my favourite story is of the Matthaei-Nirenberg experiment in 1961 (chapter 10, Enter The Outsiders). Marshall Nirenberg was the prime mover in this story, which was pegged on the race to map the nucleotide triplets to the amino acids they coded for. The experiment was significant because it ignored one of Francis Crick’s theories, popular at the time, that a particular kind of triplet couldn’t code for an amino acid. The experiment roundly drubbed this theory, and in the process delivered a much-needed dent to the circle of self-assured biologists who took Crick’s words as gospel. Another way the experiment triumphed was by showing that ‘outsiders’ (i.e. non-geneticists like the biochemists that Nirenberg and Heinrich) could also contribute to DNA research, and how an acceptance of this fact was commonly preceded by resentment from the wider community. Cobb writes:

Matthew Meselson later explained the widespread surprise that was felt about Nirenberg’s success, in terms of the social dynamics of science: “… there is a terrible snobbery that either a person who’s speaking is someone who’s in the club and you know him, or else his results are unlikely to be correct. And here was some guy named Marshall Nirenberg; his results were unlikely to be correct, because he wasn’t in the club. And nobody bothered to be there to hear him.”

This explanation is reinforced by a private letter to Crick, written in November 1961 by the Nobel laureate Fritz Lipmann, which celebrated the impact of Nirenberg’s discovery but nevertheless referred to him as ‘this fellow Nirenberg’. In October 1961, Alex Rich wrote to Crick praising Nirenberg’s contribution but wondering, quite legitimately, ‘why it took the last year or two for anyone to try the experiment, since it was reasonably obvious’. Jacob later claimed that the Paris group had thought about it but only as a joke – ‘we were absolutely convinced that nothing would have come from that’, he said – presumably because Crick’s theory of a commaless code showed that a monotonous polynucleotide signal was meaningless. Brenner was frank: ‘It didn’t occur to us to use synthetic polymers.’ Nirenberg and Matthaei had seen something that the main participants in the race to crack the genetic code had been unable to imagine. Some later responses were less generous: Gunther Stent of the phage group implied to generations of students who read his textbook that the whole thing had happened more or less by accident, while others confounded the various phases of Matthaei and Nirenberg’s work and suggested that the poly(U) had been added as a negative control, which was not expected to work.

A number of such episodes studded throughout the book make it an invaluable addition to a science-enthusiast’s bookshelf. In fact, if something has to be wrong at all, it’s the book’s finishing. In a move that is becoming custom, the last hundred or so pages are devoted to discussing genetic modification and CRISPR/Cas9, a technique and a tool that will surely shape the future of modern genetics but in a way nobody is quite sure of yet. This uncertainty is pretty well-established in the sense that it’s okay to be confused about where the use of these entities is taking us. However, this also means that every detailed discussion about these entities has become repetitive. Neither Cobb nor Mukherjee are able to add anything new on this front that, in some sense, hasn’t already been touched upon. (Silver lining: the books do teach us to better articulate our confusion.)

Verdict: 4/5

Awards week

I went into this year’s Nobel Prize Announcements Week a little confused about why I was excited. For me the prizes have always highlighted the recipients’ work, and that’s likelier than not a field of study I’ve probably never heard of (with the exceptions being physics – though I don’t presume I’m familiar with all of it – and, occasionally, literature), but then I’m also forced to think about whether the institution of the prizes isn’t becoming outmoded. It probably is; in fact, with physics I can say more forcefully that many of its rules already are out of another era.

But before I could write the obligatory criticism, an amazing article by Roberta Sinatra et al appeared in Nature Physics, titled A century of physics. Using Web of Science data, it discusses not just how and why the breadth of physics literature has increased over the years but also the motivations of the various sub-fields that have emerged under physics – especially concerning the growing need for multidisciplinarity, a topic that the Nobel Prizes for physics aren’t equipped to acknowledge. Check the piece out if you’ve the time, it’s deliciously detailed.

Anyway, as the announcements started to roll in, it was simply fortunate that the first two (for medicine/physiology and physics) afforded critical perspectives on India – allowing me to substitute the “Are the Nobels important” question with the “Is this how we screwed up” question. You could argue that this is in fact a subtle acknowledgement of the Nobel Prizes’ importance – it is but only insofar as I can say “Here’s what not winning a Nobel tells us about how we’re screwing up in xyz situations”. To wit: With the medicine prize, I used the example of Youyou Tu’s finding artemisinin with the guidance of an ancient Chinese text to look at how India’s popularising its ancient knowledge the wrong way. An excerpt:

And here emerges an instructive lesson about what Tu did differently – to not just extract artemisinin but also to preserve the dignity as well as intellectual context of Ge Hong’s work in which she found her answer. After she extracted an effective form of artemisinin in 1972, Tu arranged for its structure to be studied at the Chinese Academy of Sciences in 1975, performed clinical trials in accordance with the best practices of the field by 1977, published her research (though not in English until the 1980s due to the prevailing political environment), and finally participated in the study of large-scale production mechanisms.

What was demonstrated at the ISC in January, on the other hand, belies a lazier attempt at translating old knowledge into newer contexts. The current government’s support for phylotherapy allows researchers to forward non-peer-reviewed results in obscure, self-published journals that do nothing to advance its contents’ credibility when a better alternative would have been to organise and digitise the literature, make it more accessible, and support credible institutions in exploring the knowledge – blend the ancient with the modern, so to speak.

The physics prize was easier to connect to India: it went for the discovery of neutrino oscillations, to study which India is supposed to be building a neutrino observatory but isn’t thanks to political impediments (though not entirely environmental impediments). Again, an excerpt:

Building on similarly advanced principles of detection, India and China are also constructing neutrino detectors.

At least, India is supposed to be. China on the other hand has been labouring away for about a year now in building the Jiangmen Underground Neutrino Observatory (JUNO). India’s efforts with the India-based Neutrino Observatory (INO) in Theni, Tamil Nadu have, on the other hand, ground to a halt. The working principles behind both INO and JUNO are targeted at answering the mass-ordering questions. And if answered, it would almost definitely warrant a Nobel Prize in the future.

INO’s construction has been delayed because of a combination of festering reasons with no end in sight. The observatory’s detector is a 50,000-ton instrument called the iron calorimeter that is to be buried underneath a kilometre of rock so as to filter all particles but neutrinos out. To acquire such a natural shield, the principal institutions involved in its construction – the Department of Atomic Energy (DAE) and the Institute of Mathematical Sciences, Chennai (Matscience) – have planned to hollow out a hill and situate the INO in the resulting ‘cave’. But despite clearances acquired from various pollution control boards as well as from the people living in the area, the collaboration has faced repeated resistance from environmental activists as well as politicians who, members of the collaboration allege, are only involved for securing political mileage.

I like to imagine that such analytical comparisons are a curious, twisted reflection of a larger trend playing out in my glorious country. While the way we’re doing some of our science and pseudoscience is actively repelling international recognition, many winners of the prestigious Sahitya Akademi award, conferred for literary excellence, are returning their trophies decrying Prime Minister Narendra Modi’s silence over the Dadri lynching incident as well as the religiously motivated persecution and murder of rationalists that Nayantara Sahgal, who kicked off the returnings, called a “reign of terror”.

Circling back: The chemistry prize, however, I couldn’t make much sense of. My friend Akshat Rathi was quicker: for example, he told me how the prize, for “mechanistic studies of DNA repairs”, had overlooked this year’s Lasker Award winners (traditionally, these awardees are likelier to be Nobel Laureates). And finally, the literature prize – announced today – was a brilliant stroke of luck simply because it was awarded to Svetlana Alexievich, two of whose books I’ve actually read (one of which I highly recommend: Voices from Chernobyl). I wrote about her here.

Incidentally, The Wire also had a couple pieces concerning the Nobel Prize before the announcements rolled in: one to talk about the CRISPR/Cas9 tool for gene editing by Nandita Jayaraj and another, by me, that discussed plausible reasons why three particular Indians were passed up for the prize (M.K. Gandhi, Meghnad Saha and Satyen Bose).