A six-year-old girl in China died in March 2025 after receiving what researchers said they believed was the world’s first base-editing therapy directed at the brain, according to an investigation by Science and Retraction Watch.

The investigation has raised important questions about the oversight of an experimental personalised gene-editing trial and the way the researchers and their institutions communicated their choices.

The girl had Snijders Blok-Campeau syndrome, a rare neurodevelopmental disorder caused by a mutation in the CHD3 gene. Although the condition affects intellectual development and its severity varies widely, most people with the condition live full lives.

But that such a case could still clear the bar for an unprecedented, high-risk brain intervention says something about a society uneasy with disability and enamoured of techno-scientific interventions.

The girl’s parents sought the experimental treatment after learning of research led by neuroscientist Zilong Qiu at the Shanghai Jiao Tong University.

Base-editing is a more recent invention than CRISPR-Cas9. The American biochemist David Liu developed it at the Broad Institute in 2016 after finding a way to convert one DNA letter directly into another — say, C to T — without cutting both strands of the DNA double helix, as Cas9-based editing does.

As a result, base-editing is, in principle, more ‘gentle’ and can cause fewer unintended mutations. Its development thus renewed hopes that gene-editing could graduate from being a proof of concept and to treating rare disorders caused by defects in single genes.

That said, the memory of He Jiankui, the Chinese scientist who announced in 2018 that he had edited the genomes of twin girls at the embryonic stage without adequate ethical review, scientific justification, and even disclosure to his own university, has weighed heavily on the field.

He was later sentenced to three years in prison for his actions, and the episode forced China to tighten its rules on human gene-editing research. But as the new investigation by Science and Retraction Watch has found, the rifts between what the law says and how it is enforced have remained wide enough for a similar failure to recur.

Dr. Qiu’s team developed a personalised base-editing therapy designed to correct the genetic mutation in the child’s brain cells.

However, delivering the ‘editor’ to the brain required the researchers to inject large doses of adeno-associated viruses (AAVs), which are known to carry risks of severe immune reactions.

According to the investigation report, the child’s parents helped finance much of the therapy’s development, contributing around $860,000 (Rs 8.3 crore) from their personal savings and money borrowed from relatives.

The treatment proceeded as a clinical trial initiated by the investigator at the Xinhua Hospital in Shanghai. This process did not require the National Medical Products Administration, China’s national drug regulator, to review it first.

However, the report has quoted independent experts expressing concerns with several aspects of the process — including whether preclinical studies (in animals) had adequately proved the treatment’s safety for human use.

Toxicology studies in monkeys reportedly found that all the treated animals had developed liver injury and one monkey’s kidneys were damaged as well.

However, the researchers proceeded to inject the therapy into the girl’s cerebrospinal fluid on March 24, 2025. Within days, she developed a fever and kidney damage, and died a week later.

An internal review at the hospital concluded that the treatment was certainly linked to her death, and listed the cause of death as thrombotic microangiopathy, a complication that has previously been associated with genetic therapies involving high doses of AAVs.

According to Science and Retraction Watch, neither the researchers nor the hospital disclosed the girl’s death at the time. Several months later, local health authorities fined the hospital for shortcomings in trial oversight and registration, but did not sanction the lead researcher.

The family said they later asked that a research paper related to the trial be withdrawn, arguing that it did not reflect the appropriate outcomes.

The investigation also examined a paper published in Nature earlier this year describing the underlying preclinical work. Some independent experts questioned aspects of the reported data and argued that the journal should examine the underlying evidence and funding disclosures.

Nature said it had not been informed of the patient’s death or the regulatory issues before publication and that such information would have been considered during editorial review.

The case has prompted renewed debate about ‘first in human’ gene-editing trials, particularly for rare but serious disorders.

In June 2024, Nature had reported a similar story in India: researchers across the country raced against time to develop a treatment for Uditi Saraf, a 20-year old with familial encephalopathy with neuroserpin inclusion bodies, or FENIB — a rare and aggressive brain disorder with symptoms similar to dementia.

Sadly, Uditi passed away before the treatment was ready, although the Sarafs, who helped fund the tests, and the researchers expressed hope afterwards that their efforts could help other people with FENIB.

The researchers’ challenges included identifying the mutation, engineering the base-editor, manufacturing the AAV vectors, and improving institutional capacity to produce a gene therapy of direct clinical value.

Both instances — Uditi Saraf and the little girl in China — began with researchers committing themselves to a schedule they knew would be uncertain and high-pressure.

But in Uditi’s case, while the researchers worked 12-hour days and called in favours from colleagues abroad, their efforts also had to contend against the friction of collaborating across borders and dealing with the US’s more cautious regulatory system. In India as well, Arkasubhra Ghosh at Narayana Nethralaya Eye Hospital was waiting for approval from Indian regulators to manufacture AAVs when Uditi passed away.

In China, on the other hand, the researchers faced little resistance going from decision to injection.

Of course, this doesn’t mean India treats disability better than China. Stigma against disabled people here is widespread, sustained by misunderstanding, misinformation, and prejudice.

The Sarafs’ experience also opened a window to India’s opportunity to become a centre for affordable gene-editing as it wound through Ghosh’s ambition to manufacture AAVs within the country and Debojyoti Chakraborty’s efforts at the CSIR-Institute of Genomics and Integrative Biology to develop inexpensive CRISPR therapies.

That said, while India offered the possibility of acting before it was too late, the researchers might have faced similar questions over the preclinical evidence and toxicology reports and regulatory penalties against hospitals if the treatment had gone awry.

Finally, none of the regulatory philosophies at work in these episodes guarantees success. One emphasised exhaustive reviews before ‘first in human’ use. Another allowed investigator-initiated trials to proceed more rapidly. A third was willing to devolve trust based on reputation and clinical stature over external reviews, including of safety.

In fact, while the law in China forbids charging patients for unproven therapy, it is also written narrowly enough for informal payments to individual researchers — such as the gifts to Dr. Qiu — to fall outside its purview.

Communicating risk and the possibility of death also have thorny social dimensions, including the optimism surrounding frontier biotechnologies and the emotional entanglement that can develop between families and researchers.

Textbooks have said for decades that haemoglobin is found in the red blood cells (RBCs), that it makes blood red, carries oxygen, and is essential for our survival.

A new and serendipitous discovery has revealed that haemoglobin isn’t used by RBCs alone. In a study published in Nature, scientists from China have reported that chondrocytes – cells that make cartilage, the connecting tissue between bones – also make haemoglobin and seem to depend on it for their survival.

‘Haemoglobin bodies’

Feng Zhang, a pathologist in the Fourth Military Medical University in China, had been working on bone development since 2010. In 2017, when he was studying growth plates – cartilaginous tissue at the end of certain long bones that allows the bones to become longer – he stumbled upon a few spherical blob-like structures. They seemed to bear an uncanny resemblance to RBCs, and they contained haemoglobin.

Dr. Zhang then teamed up with Quiang Sun at the Beijing Institute of Biotechnology and used advanced microscopy techniques to investigate further.

Picture what happens when oil is mixed into water: the oil separates out into little globules in a process called phase separation. That’s what seemed to be happening in the chondrocytes in the cartilage as well. Dr. Zhang ascertained that the chondrocytes within the growth plates of newborn mice were not only producing large amounts of haemoglobin, but also that it was coalescing and forming large blobs without a membrane.

The scientists called these blobs haemoglobin bodies, or Hedy.

The haemoglobin does something

Now that they knew chondrocytes were making haemoglobin bodies, the question was: were the Hedy functional? That is, did they actually do something? To test this, the scientists used genetically modified mice, in this case mice in which the gene making haemoglobin had been removed. These mice produced almost no haemoglobin molecules and they died as embryos. But it turned out that if one looked closely at the growth plate cartilage tissue from these mice, most of the chondrocytes were dying.

Removing the gene that made haemoglobin specifically in the cartilage tissue also resulted in the same outcome: cell death among the chondrocytes. It was clear that Hedy was essential for the chondrocytes to live.

In RBCs, haemoglobin carries oxygen and makes sure that different parts of the body receive the oxygen to function correctly. The scientists conducted a series of experiments to check whether haemoglobin also carries oxygen in chondrocytes. First, they checked if the cartilage cells showed signs of stress before dying when haemoglobin molecules were absent. They focused on a special type of stress called hypoxic stress, caused by low-oxygen conditions. And indeed they did: cartilage that didn’t contain haemoglobin showed signs of hypoxic stress.

An oxygen store

Now they knew that the absence of haemoglobin caused the chondrocytes to go through some sort of low-oxygen stress. They then wanted to see how normal and haemoglobin-free chondrocytes behaved when there is little oxygen in the cells’ environment. The researchers proceeded to test the cells in a low-oxygen, or hypoxic, environment. In the presence of haemoglobin, the cells seemed to release more oxygen. But in the absence of haemoglobin, the chondrocytes started dying.

This further confirmed their hunch that the haemoglobin in the chondrocytes was most likely storing oxygen and supplying it to the cells when required.

“What’s really interesting about this paper is that they picked up on this unusual finding and delved deep into its aspects,” said Noriaki Ono, a bone biologist at the University of Texas Health Science Center at Houston. He wasn’t involved in the study.

Haemoglobin in other places

In a developing growth plate, where oxygen is limited due to a lack of blood supply to the region, the chondrocytes still manage to thrive. Based on the scientists’ findings, it’s the haemoglobin molecules that manage to bring them the oxygen they need to survive.

“What surprised me the most was that cartilage tissue synthesised a large amount of hemoglobin to cope with hypoxic stress,” Dr. Zhang told this writer by email.

A 2003 study had shown that chondrocytes adapt to low oxygen by, among other things, using an alternate pathway to break down sugars to release energy – one that doesn’t require oxygen. This study shed light on a different mechanism with which chondrocytes dealt with reduced oxygen supply.

The scientists also found that cartilage in regions outside the growth plate, like the one in the ribs or the spine of mice, also contained haemoglobin. What we don’t know yet for sure is whether the haemoglobin in these regions plays a similar role, in storing and releasing oxygen.

‘Really exciting possibility’

“What is important in this paper is that it breaks down barriers between haematology and skeletal biology, and shows that, in fact, these fields are more connected than it seems,” said Gerard Karsenty, a professor studying skeletal biology at Columbia University, New York.

We also don’t know if the Hedy has more functions or other effects on cells in the growth plate. Dr. Ono, who discovered a bone-making stem cell population in the growth plate in 2018, is intrigued by the possibilities this discovery opens for stem cells and their fates in the growth plate. “One really exciting possibility is that the haemoglobin in the growth plate could be doing something about changing the … fate of stem cells in the growth plate,” he said.

The discovery of functional haemoglobin in cartilage also leads to the possibility that it plays a role in certain joint diseases. “There are many bone deformities that develop from defects in chondrocytes,” according to Dr. Ono. “Maybe there is more cell death in some conditions due to having something wrong with the chondrocyte haemoglobin.”

Dr. Zhang added that he “hopes this discovery can reinterpret the mechanisms underlying some joint diseases.”

Rohini Subrahmanyam is a freelance journalist.