Primary Topic
This episode delves into the groundbreaking yet challenging application of CRISPR genome editing to treat a rare genetic disease in a young woman, highlighting the intersection of advanced science and personal struggle.
Episode Summary
Main Takeaways
- CRISPR genome editing holds immense potential for treating rare genetic disorders.
- The development of such therapies is time-sensitive, often racing against the progression of diseases.
- Collaboration between global researchers and localized efforts in countries like India are vital for advancing affordable gene therapies.
- The personal stories of patients and families are deeply intertwined with scientific endeavors, driving researchers to push boundaries.
- Despite the promise of genome editing, the reality involves significant technical, regulatory, and ethical challenges.
Episode Chapters
1. Introduction
Benjamin Thompson introduces the episode's focus on the innovative use of CRISPR to treat a rare genetic condition. He sets the stage for a deep dive into the complexities of personalized medicine and the race against time. Benjamin Thompson: "In this episode, we explore the race to save one woman's life through the lens of CRISPR genome editing."
2. The Challenge
The chapter details the initial meeting with Uditi and the scientific challenges faced by the team as they develop a novel treatment. Benjamin Thompson: "Researchers were racing to design a treatment that would edit DNA in brain cells to stop producing toxic proteins."
3. Progress and Setbacks
This section covers the rapid progress towards a therapy and the tragic setbacks, including Uditi's worsening condition and the global impact of the COVID-19 pandemic. Benjamin Thompson: "The pace of scientific research was too slow for Uditi's rapidly progressing disease."
4. Hope and Despair
The emotional and scientific rollercoaster experienced by Uditi's family and the research team as they navigate the possibilities and limitations of CRISPR therapy. Benjamin Thompson: "It truly is a story of hope, amidst the backdrop of despair as the disease took hold."
5. Reflections and Legacy
The concluding chapter reflects on the lessons learned from Uditi's case and the potential future impact of this research on other rare diseases. Benjamin Thompson: "Despite Uditi's tragic death, the lessons learned will help others on a similar path."
Actionable Advice
- Advocate for research in rare diseases.
- Support genetic testing and early diagnosis.
- Encourage collaboration between global and local research teams.
- Educate about the potential and limitations of CRISPR.
- Promote funding for rare genetic disorders research.
About This Episode
In India, a group of researchers raced to develop a CRISPR-based genome editing therapy to save the life of a young woman with a rare neurodegenerative disease. Despite a valiant effort, the pace of research was ultimately too slow to save her life. While many are convinced that these therapies could offer hope to those with overlooked genetic conditions, it will likely take years to develop the techniques needed to quickly create bespoke treatments, something people in need don't have.
People
Jennifer Doudna, Arkashubra Ghosh, Benjamin Thompson, Uditi Seraf, Sonam Seraf, Rajiv Seraf
Companies
Narayana Nathralia Eye Hospital, NYU Langone Health, Council of Scientific and Industrial Research
Books
None
Guest Name(s):
None
Content Warnings:
None
Transcript
Nature Podcast
The Nature podcast is supported by Nature Plus, a flexible monthly subscription that grants immediate online access to the science journal Nature and over 50 other journals from the Nature portfolio.
More information at go dot nature.com.
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Benjamin Thompson
This is an audio long read from nature. In this episode, hope, despair, and crispr the race to save one woman's life, written by Heidi Ledford and read by me Benjamin Thompson.
When researcher Arkashubra Ghosh finally met Uditi Seraf, he hoped there was still a chance to save her.
Gosch and his collaborators were racing to design a one off treatment that would edit the DNA in the 20 year old woman's brain cells and get them to stop producing toxic proteins.
It was an approach that had never been tried before, with a long list of reasons for why it might not work.
But the team was making swift progress.
The researchers were maybe six months away from being ready to give Uditi the therapy, Kosh told her parents over breakfast at their home outside New Delhi last June.
Even so, Uditzis mother was not satisfied. Work faster, she urged him.
Then Udity was carried to the breakfast table, and Gosch understood her urgency.
Once a gregarious and energetic child and teenager with a quick laugh and a mischievous streak, Uditi was now unable to walk or feed herself.
She had become nearly blind and deaf.
Her family tried to talk to her. These are the people who are making a therapy for you, they said. Loudly.
Shaken, Gosch returned to his gene therapy laboratory at Narayana Nathralia Eye Hospital in Bengaluru, India, and got to work.
If you need to put up tents in the lab, then we can do so, he told his students. I'm not going to sleep.
Four months later, Uditi was gone.
The first therapy using CRISPR genome editing was approved in late 2023 to treat blood disorders that affect thousands of people worldwide.
But the approach is also a source of hope to many people who have extremely rare genetic conditions, like the one udity had.
Genome editing could one day become a radical way to address the diseases that are overlooked by pharmaceutical companies.
Patients are waiting. Families are waiting, says Jennifer Doudna, a molecular biologist at the University of California, Berkeley. So we need to get on with it.
Researchers are still laying the groundwork for this future.
They are working out how best to design and manufacture the treatments, and how to deliver them to precise locations in the body.
The cost is also a problem.
The price of genome editing therapy threatens to put it out of reach for many.
Gosch wants to bring those barriers down, and hes convinced that India will eventually be the country to do it.
But uditis family could not wait. The pace of scientific research was too slow. They needed a sprint and a team of researchers willing to take on not only the scientific challenge but also the emotional heft and high risk of failure involved in attempting something that had never been done before.
What we were trying to do was really almost in the realms of science fiction, Gosch says.
And he remains convinced that despite uditis tragic death, the lessons learnt will help others on a similar path.
It truly is a story of hope.
As a young girl, udity was always in a hurry. Seizing any excuse to celebrate, whether it was a birthday or a festival. She would buzz around the house, getting ready hours ahead of everyone else, peppering her mother with urgent requests.
She greeted family and friends with cuddles and kisses, and brightened parties with her laughter and dancing.
For the first nine years, there was no hint of trouble. And when it began, it was just a flicker, a few seconds here and there. When oodity would zone out, she'd switch back on again, as if nothing had happened. And her mother, Sonam, wasn't sure if she should worry.
But then Sonam saw nine year old Uditi drop a camera on the floor and become confused as to why it was no longer in her hand, a mothers hunch hardened. Something was wrong.
The physicians diagnosed her with epilepsy.
When Uditis seizures became more pronounced and she began to struggle at school, Sonam and Rajiv Uditis father decided it must be something more.
In 2017, they had part of oodity's genome sequenced.
It was a deviation from the standard treatment path, but the seraphs were technologically savvy and financially well off.
In India, as in many places in the world, genome sequencing was still uncommon, its rollout slowed both by the costs and by the dearth of genetic information from people of indian descent in genetic databases.
Without such data, it can be difficult to interpret sequencing results.
Udity's results, however, were unambiguous. A single base change in the gene that codes for a protein called neuroserpin caused tangled polymers to form in her brain cells, interfering with their function. Udity's neurons were dying.
This condition is called phenib familial encephalopathy, with neurosurpin inclusion bodies and the symptoms, which can be similar to dementia, usually manifest late in life.
Eleanor Miranda, a cell biologist at the Sapienza University of Rome, runs the world's only lab that focuses on the disease. She says that it's possible that many cases of phenib go unreported because physicians do not often sequence the genomes of older adults with dementia.
But the most severe forms of phenib strike early and are exceedingly rare.
Miranda had known of only three other people with the same mutation that Udity had.
This form of the disease is very aggressive, she says.
Udity and her parents embarked on a lonely journey familiar to many people with rare diseases. They had never heard of pheinib, and neither had Uditi's physicians.
Sonam did some research but couldn't bring herself to fully absorb what she found.
We thought it's not possible, she says. It cannot happen with our daughter.
The seraphs 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.
We shopped for doctors, we shopped for gods, says Sonam. But Udity's condition slowly worsened.
The three moved to upstate New York in 2018 to send Udity to a school for people with disabilities.
Her seizures intensified, and frequent muscle spasms made it hard for her to walk or drink from a glass.
Her bright personality was dimming. The Seraphs discussed experimental treatments with Udity's new physician, epilepsy specialist Orin da Vinsky at NYU Langone Health in New York City.
Davinsky mentioned a couple of options, one of which was CRISPR genome editing.
Rajiv seized on the idea oudertys disease was caused by a mutation that converts a single DNA base from a g to an a variation on CRISPR genome editing, called base editing, could theoretically correct exactly this kind of mutation.
Da Vinsky also emphasized the difficulties at that time. Base editing, which was first reported in 2016, had never been tested in a clinical trial.
The technique requires shuttling a relatively large protein and a snippet of rna into affected cells. Researchers were struggling with how to perfect this delivery for many organs, the brain being one of the most daunting.
Even if each of these hurdles were surmounted, at best, base editing might stop the production of neurosurpine clumps in some of UDa's neurons.
The treatment was unlikely to reach all affected cells, and it was unlikely to clear the clumps that were already present or to regenerate neurons that had been lost.
But Rajiv and Sonam saw an opportunity for hope.
Perhaps such a therapy could slow down the progression of Oudertis disease, buying time for scientists to develop another treatment that could repair the damage that had been done. The Seraphs were on board.
Da Vinsky assembled a team at NYU Langone Health with expertise in genome editing and neuroscience to conduct preliminary studies of the approach.
The researchers pulled together what funding they could from other grants, and the Seraphs funded the rest.
We will sell our house if we have to, Sonam said.
The pressure in the lab was intense, says team member Jaita Basu, a neuroscientist at NYU Langone Health.
The team genetically engineered Udity's phenib mutation into cells grown in the lab.
When the cells initially didn't seem to behave as expected, Basu asked her graduate student to repeat the experiment five times.
I was always pushing, she says. We had to be fast, but we also had to be diligent. There was no shortcut.
In December 2019, the Seraphs moved back to India.
Maintaining a home in the United States was expensive, and Uditi missed her extended family.
Then the Covid-19 pandemic struck, and in January 2021, Udity 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 udity, and she began to pace the house incessantly, rarely even going to sleep.
The seraphs decided to speed up the base editing project by funding a second team in India.
Meanwhile, DA Vinsky had petitioned a us foundation to devise a different experimental treatment called antisense therapy for udity.
The family flew from India to the United States twice for injections into her spine.
The trips became traumatic as her ability to understand the world around her declined.
The treatments didn't work, and the experience taught Rajiv and Sonam how long it could take to get approval to try an experimental therapy in the United States.
They decided uditis base editing therapy should also be manufactured and administered in India, about an hour and a half away from their home. Dibuchati Chakraborty, a geneticist at the Council of Scientific and Industrial Research's Institute of Genomics and Integrative Biology in New Delhi, had been making headlines for his efforts to devise a CRISPR based treatment for a genetic blood disorder called sickle cell disease.
Researchers in the United States were also developing genome editing therapies for sickle cell disease, but those therapies were expected to be expensive and potentially out of reach for much of the world. The UK Medicines and Healthcare products Regulatory agency approved the first one, Caszevi, made by vertex Pharmaceuticals in Boston, Massachusetts, and CRISPR Therapeutics in Zug, Switzerland, which costs $2.2 million per patient.
Most of the people with sickle cell disease in India, a country with one of the highest rates of the condition, live in impoverished communities.
Chakraborty and his colleagues hope to develop a therapy that could be produced and administered at a fraction of the price that is charged in the United States, if not less.
Rajiv and Sonam went to the institute to talk to Chakraborty and the institute's director, chemist Sawvik Mighty, who had been collaborating with Chakraborty on the CRISPR technology behind the sickle cell project.
Although the institute gets many requests for help from people with rare diseases and their caregivers, the seraphs were unusual in that they would be able to help fund the work, says my tea. Uditi was the only person in India known to have her neurosurpin mutation, and no government agency, company or philanthropy was likely to pay for the development of her treatment.
It's very difficult, Mighty says.
Even if our heart is telling us we should work on it. Until there is funding, we cannot do it even with funding. Mighty and Chakraborty took some time to discuss the project with Gosch, who was building a facility in Bengaluru to produce viruses called adeno associated viruses, or aavs, which are often used in gene therapies.
Gosch aimed for his facility to be one of the first in India to produce aavs to the standards required for use in people.
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 Gosch's facility approved by India's regulators for producing the base editing components.
Udity's illness had probably already progressed beyond the point at which the therapy could offer a notable benefit, but the family wanted them to try, reasoning that the work that they did on this project could help future endeavours to develop genome editing therapies for genetic conditions.
It was not the first time Gosch was swayed by a personal appeal.
A few years before he met Udity, Gosch came to work and found two women waiting outside of his office. They would not leave, the women said, until he had committed to finding a treatment for their young son's illness, a genetic condition called Duchenne muscular dystrophy, which can be fatal.
The women pledged to help raise funds, and Ghosh found himself unable to say no. He has worked on the project and grown close to the families since then.
Lab protocols for making medicines are notoriously strict, with each step carefully controlled to minimize the chance of contamination.
When setting up his facility for manufacturing gene therapies, Gosch scrutinized each step, looking for ways to cut costs without sacrificing safety, arguing his case to India's regulators.
He estimates that gene therapies for eye diseases that are developed in his lab will one day be available for 100th of what they cost in the United States.
We will certainly short circuit this entire field, Gosch says.
India has earned a reputation for making complex drugs on a budget.
During the Covid-19 pandemic, indian manufacturers cranked out millions of doses of vaccines.
Now the country is manufacturing a malaria vaccine at a fraction of the cost of that in Europe and is developing sophisticated cell and gene therapies used in cancer treatments for much less than the price of those in the United States.
Chakraborty took the lead on uditis project.
He is a go getter kind of person, says Rhea Routhan, who was then a PhD student in Chakraborty's lab. He is not bothered by who he needs to ask to get something done. He just does it.
To minimize interruptions, the team mapped out all of the experiments and the components they would need from start to finish. In India, many lab reagents have to be imported, and supply interruptions can delay projects by weeks or months.
Everything had to be planned and ordered ahead of time, and mighty worked to keep the supplies coming, seeking out vendors and negotiating prices.
Time was more valuable than anything else, he says.
One of the most important reagents had to come from abroad, antibodies that could recognize the neurosurpine protein and its tangles. Few researchers used such antibodies, and the supply was uncertain.
The team decided that the quickest way to get reliable antibodies was to ask Miranda in Rome to share the ones she had developed. She gladly did.
This was a desperate approach, she says. But for me, the priority was to try to help as much as I could.
Rauth then generated stem cells from samples of udesis blood. Then she and her colleagues coaxed those cells to become neurons and used base editing on them. In the lab, Gosch worked on preparing the aav that would be used to transport the CRISPR components into uditis neurons.
The team needed to determine which strain of aav would work best.
Some strains could trigger inflammation in the brain. Gosch's lab tested several types of aav in mice to find out which one caused the least amount of inflammation and how best to administer it.
The team eventually settled on one type, called aav nine, and determined that it should be injected directly into uditis brain.
Still, that was not the end of their challenges. Aav genomes can carry only an extra 4700 DNA bases, but the gene that codes for the enzyme needed in base editing is longer than that.
Gosch and his students worked to divide up their genomic cargo so that it could fit into two separate viruses and added sequences that would allow the two pieces to be spliced together again when they are expressed inside a cell, the team will inject both viruses at the same time.
The approach has been shown to work in mice, but has not yet been tested in humans.
By June 2023, the team seemed to be barreling towards the finish line.
Many of the researchers were working ten to twelve hour days, and it was nearly time to test their therapy in mice.
Gosch was also scheduling a regulatory inspection to ensure that he would have the approvals he needed. By the time the animal results were in, a surgeon had agreed to perform uditis injection.
If all went well, they might be ready to treat Uditi in as little as six months, Chakraborty predicted.
In early October, a few months after Chakraborty and Gosh had breakfast with Uditi and her parents, the team received a series of messages from Rajiv on their WhatsApp group. Uditi had become ill with pneumonia and had been taken to the hospital.
Then she was in a coma and had been sent home. There was nothing else the physicians could do for her.
Soon afterwards came the message they had all feared. Oudity was gone.
Ghosh thought immediately of the two little boys with Duchenne muscular dystrophy. What if I'm too late for them, too?
Others in the lab also took the news hard for clinicians. Perhaps they become hardened, says Chakraborty.
We dont have that experience.
We were feeling agony.
Ten days after learning that Urati died, Chakraborty presented the labs efforts at a local conference and finished his talk with a picture of Uriti smiling in the audience. Rhea Patra, a graduate student in Goschs lab, began to cry.
It was the first time shed let herself see a picture of the young woman she tried so hard to save.
Before, I had thought that if I saw her, maybe I would cry, she says, and I wouldn't be able to work anymore.
An estimated 100 million people in India have a rare disease.
For decades, people affected by such conditions have cycled through hope and disappointment as researchers have inched closer to developing therapies that can help them at a genetic level.
After a series of sporadic starts and failures, gene therapy has finally begun to find its footing.
This has set the stage for CRISPR based genome editing to rocket to the clinic when nine year old Uditi first dropped her camera. CRISpR was just an oddity, a strange assembly of sequences found in microbial genomes only studied by a few die hard microbiologists.
Four years before she was diagnosed with venib, researchers showed that for the first time, a CRISPR based system could cut DNA in human cells grown in the lab.
The first CRISPR based genome editing therapy was approved in the United Kingdom to treat sickle cell disease the month after Uditi died.
In theory, many people with a genetic condition, no matter how rare, could benefit from these technologies. But the reality is harsher. 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, but researchers are working to streamline the process.
Doudna's institute, for example, is working to standardise some aspects of genome editing therapies, in part to make it cheaper and easier to develop such treatments for people with rare conditions.
And the US National Institutes of Health has been trying to develop similar pipelines for gene therapies, an effort that could help to inform gene editing efforts. Its been really hard, says Doudna. But what were doing is going to have long term impact in India. The work has continued. Rajiv has urged Chakraborty to finish the teams studies in mice so that the next person with phenib will not have to wait as long for a potential treatment.
Some of the work will be completed, and the efforts could benefit others with genetic conditions that affect the brain, particularly in India.
We are not really trying as aggressively as we did earlier, he says. But that technology has a lot of potential.
At Uditis memorial service, Rajiv tried to make sense of the timing.
Uditi was always in a hurry, he told attendees. She always had to be first.
She was only a few months away from receiving an experimental treatment, but she would not wait, not even for that.
She could not let science win. He said she was always ahead.
To read more of Nature's long form journalism, head over to nature.com news.
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