There's so many ethical problems with the events as described in the article. The worst to me seems to be that the researchers/doctors seem to have downplayed the risks here. Which for a never before tried gene therapy that is meant to work inside the brain are absolutely enormous. The ethical issues around the money seem minor in comparison with that and the fact that they seem to have ignored similar side effects in the monkey experiments.
This is the EXACT reason why the FDA exists.... this.... shit.... tricking desperate parents into paying millions of desperate dollars when anyone who knows anything about it knows the "experiments" just cause death. Yet another grift.
Were there any actual doctors in the researchers ? They should have their license immediately revoked for omitting side-effects, thus breaching their oath.But this is China, so I am not sure there will be accountability, unless this get even more attention.
> The paper had an enthusiastic reception. “These promising results might pave the way for the development of an effective clinical treatment,” Kevin Bender, a neuroscientist at UC San Francisco, wrote in an accompanying commentary. At the time, Bender had no idea that a girl had received it and was already dead. Meanwhile, Chinese state media, CCTV, called the work “the first ray of hope” for “countless families suffering such diseases.”
Oof, there's something deeply unjust about that, a kind of "adding insult to fatality."
People celebrating that a new treatment will save children and give hope... with no acknowledgement that it was just tried and cost you both.
> The young girl tugged on her mother’s hand as they pressed through the doors of the hospital in Shanghai. She was 6 years old, bouncing along in a pink jacket and blue pants decorated with cartoon bears. Behind them, her father rolled a large suitcase with everything the child needed for the weeklong stay: stuffed animals, Play-Doh, an iPad loaded with episodes of Peppa Pig.
What's this style of "journalism" (time-wasting) called and how can we exterminate it?
> When Mei was 4, one of her kindergarten teachers pulled Linda aside: Mei didn’t draw or write as well as the other kids and her language skills weren’t developing normally. Her mother might want to get her evaluated, the teacher said. In March 2023, Mei was diagnosed with global developmental delay, a broad label with many causes. Specialists explained that some of Mei’s behaviors—the funny sounds she liked to make, for instance—were associated with autism.
- The girl had a really rare genetic disorder, traceable to a single-base mutation, that result in intellectual disability. Her case was quite mild, she was verbal and only had a learning disability, other cases are often far more severe.
- They went for using adeno-associated virus as vector to deliver a CRISPR payload. It caused kidney and liver damage (AFAIUK due to immune response, not the virus itself? So hard to predict from an animal model.) which turned out fatal.
- The family paid a significant share of the research funding and some off-record financial favors to the research team.
- The research team's recent publication in Nature didn't mention the case at all (they basically chose keep silent about failures).
The whole story has quite some Flowers for Algernon vibes except real life is way more cynical and sad. And I disliked the book back when I read it because it felt like a weepie just for the sake of weeping.
An article about the complicated issue that is a child with a non-lethal developmental disorder getting a treatment that ends with the tragedy of the headline. The article might be sensationalizing the situation, but it makes the doctor out like a monster and as the facts read I can't say I disagree.
That the treatment was inconclusive in the animal studies isn't particularly shocking. The brain is one of the more complicated parts of a human body after all. Ethics and safty concerns seemed to get ignored all the way to the actual treatment speaks like the money and potential fame was all the medical staff involved were concerned with. The parent's aren't blameless, they wanted to fix a child who probably would have lived with a below average quality of life. The article claims they were mislead to believe this treatment was safer than it actually was.
The treatment vehicle seems like the cause of death as reported toward the end, but there are words about the animal testing that imply this could have been a known risk with the treatment as a whole. The number of things being found with hindsight remind me of "move fast and break things" development. It really sounds like cutting edge (bio)tech has ethics get ignored when money and fame are on the table.
What? The monkeys all had problems! Why do this? Just do PGT for your other kids. Come on, dude! Non lethal condition. Deranged behaviour.
We did IVF with PGT and these days they tell you about carrier screening super early and everything here in California. I wouldn’t experiment on a real-life living human like this.
A last ditch effort to save a life perhaps but come on, dude.
> The tradeoff is pretty straightforward: the US system emphasizes uniform standards and upfront rigor, while China’s [investigator-initiated trial] model pushes decision-making closer to the doctor and the patient, making it easier to start trials quickly and iterate as data comes in
It's clear that they are prioritizing iteration over standardization - which is a good pathway to exploration but will yield results like this. In the end, we're all going to benefit from the new research coming out of China as they subject themselves to this high-variance policy.
This is a tragic story. But it is also a story about the lengths that parents in China will go to improve the quality of life for their only child or to "save face" to their social circle about how their child is performing relative to others.
It's quite tragic that they felt the need to lean into this treatment and quite tragic that they were led on. Just a sad story all around.
There are many children with life-threatening rare diseases that would be much better candidates for risky experimental treatment like this. Very sad case.
"Seven days after the girl’s medical team infused trillions of viruses carrying the recipe for the base editor into her spinal fluid, she died of a severe immune reaction linked to the therapy"
questions of a layman - couldn't they initially do a small infusion of the [may be even weakened version of that] viruses to check for the immune reaction? May be such infusion would really serve as a vaccine prepping the immune system for the main infusion later? - though immune system killing the viruses may be nullifying the treatment - then may be when doing such therapy the patient needs to be [somewhat] immunosuppressed similar to transplant situations?
> though immune system killing the viruses may be nullifying the treatment
That's a problem for some types of RNA/DNA vaccines where they use a virus as a vector. You can usually only use a specific kind of virus once per patient.
I'm honestly quite shocked that the physicians/scientists involved would choose to use an AAV for a brain-targeted gene therapy. There is just so much data demonstrating that these vectors are quite immunoreactive: most of the approved gene therapies based on AAVs carry black box labels for liver failure caused by an immune reaction to the viral capsid. Admittedly, AAVs are the most derisked vector for gene therapies, but infusing them directly into someone's brain and expecting nothing bad to happen is, in my view, crazy.
[Note that I work in this field and have co-founded a CNS AAV company]
This isn't the correct takeaway. AAV are one of the most complex drug modalities and carry considerable risk when used incorrectly. This story is tragic and violates pretty much every ethical consideration for a clinician researcher. Especially ones that are treating children of desperate parents.
That said, AAV are one of the most powerful delivery mechanism we have to deliver gene therapies to the brain. Uniqure has shown the first efficiacious treatment of Huntington's disease with intraparenchymal delivery of AAV5, Zolgensma is a brain targeted AAV9 to treat SMA, Kebilidi is an intraparenchymal AAV2 that treats AADC deficiency.
The general approach should be to keep dose as low as possible and minimally expose the periphery. AAV9 at large doses delivered intrathecally without standardized immunosuppression is simply insane.
This shows how important disclosures are. A field like this cannot learn if unsuccessful human experiments disappear while the corresponding animal work is published as promising.
Many years ago I was attending pre-surgery for a hip replacement surgery for my sister, who had known severe reactions to anesthesia (actually required a tracheotomy for a previous reaction). The anesthesiologist asked to speak to us privately and informed us that in their opinion, my sister had maybe a 1/3 chance of not surviving the surgery. They also mentioned that this was a breach of protocol and they could get in trouble for talking to us directly, but their conscience wouldn't let them do otherwise. We returned and asked the surgeon if they really thought the risk justified any potential benefit. The surgeon shrugged and said "probably not, feel free to call it off". Keep in mind that nobody on the care team had previously discussed any risk or indeed any tradeoffs whatsoever. This was at one of the best-regarded children's hospitals in the USA.
The lesson for me is that you must advocate for yourself and your loved ones in the medical system, because doctors will not do it for you; they may not even perform the most basic risk assessments. And you have to try to quantify risk yourself, because doctors will refuse to give you the slightest hint of any number attached to risk (I know, I've tried many times).
1/3rd chance of not surviving is like suddenly dashing across a busy freeway without looking, from a crouched position behind a bush. That's what it means to send the person into that. Yikes!
Is that even legal? Can a bunch of people decide to go ahead with performing some procedure that has a 1/3 chance of killing the person, whose life is not in danger if it is not performed? If that person dies, that's seems like murder.
All that we know is that the doctor carefully guided the patient out of the intervention, flashing a value that nobody had introduced before in the conversation. Is unclear WHY without more information.
The fair possibility is that it would be not the best choice for the patient,
But other possibility could be a schedule problem with the doctor holidays for example.
Or that it would be too expensive for the hospital
Or that they didn't have the materials or the experience
To go forward with this operations the interests of the patient, the doctor and the hospital must match. Sometimes only two parts benefit from it.
It is important to note that in China, developmental delays are treated with ridicule for the affected and as a source of shame for the families.
I'm not passing judgment on the parents, I'm just pointing out that how society treats developmental delays is extremely important to the quality of life of these people.
Here in the US autism was considered a "mental illness" until the 1980's.
Two years ago, my then 81-yr old father, who had Progressive Supranuclear Palsy, was recommended to get back surgery to relieve chronic and debilitating pain. The neurosurgeon said it's routine surgery and he's done it on people much older. We ultimately decided against it and found that a simple wedge pillow to sleep on relieved his pain. A bloody $50 pillow. And this came from a recommendation from a physiotherapist.
What's particularly galling is the recovery from back surgery would've taken at least 6-9 months of rehab and my father's PSP was already sapping his motor skills and yet the surgeon was pushing ahead.
Even with my mom I've had to intervene on several occasions against the doctor's utterly idiotic ideas. Thank goodness for AI to at least make us conversant to ask the right questions of these doctors.
Cases like this are heartbreaking, but they're also a reminder that failures like this ones need to be published just as prominently as success. Gene editing is still a young field, and if negative outcomes remain hidden, other researchers can't properly assess risks or make improvements
I am baffled by Nature saying would this have been communicated during peer-review this would have been taken into consideration, but because this was discovered after it doesn't count anymore.
It's like a teacher saying if you get caught cheating during the exam you will be punished, but if it's after you can get "scott-free."
46 comments
[ 0.48 ms ] story [ 60.7 ms ] threadOof, there's something deeply unjust about that, a kind of "adding insult to fatality."
People celebrating that a new treatment will save children and give hope... with no acknowledgement that it was just tried and cost you both.
What's this style of "journalism" (time-wasting) called and how can we exterminate it?
- The girl had a really rare genetic disorder, traceable to a single-base mutation, that result in intellectual disability. Her case was quite mild, she was verbal and only had a learning disability, other cases are often far more severe.
- They went for using adeno-associated virus as vector to deliver a CRISPR payload. It caused kidney and liver damage (AFAIUK due to immune response, not the virus itself? So hard to predict from an animal model.) which turned out fatal.
- The family paid a significant share of the research funding and some off-record financial favors to the research team.
- The research team's recent publication in Nature didn't mention the case at all (they basically chose keep silent about failures).
The whole story has quite some Flowers for Algernon vibes except real life is way more cynical and sad. And I disliked the book back when I read it because it felt like a weepie just for the sake of weeping.
That the treatment was inconclusive in the animal studies isn't particularly shocking. The brain is one of the more complicated parts of a human body after all. Ethics and safty concerns seemed to get ignored all the way to the actual treatment speaks like the money and potential fame was all the medical staff involved were concerned with. The parent's aren't blameless, they wanted to fix a child who probably would have lived with a below average quality of life. The article claims they were mislead to believe this treatment was safer than it actually was.
The treatment vehicle seems like the cause of death as reported toward the end, but there are words about the animal testing that imply this could have been a known risk with the treatment as a whole. The number of things being found with hindsight remind me of "move fast and break things" development. It really sounds like cutting edge (bio)tech has ethics get ignored when money and fame are on the table.
The fact that the parents had to make further efforts to go through their daughters death to warn others just feels wrong.
We did IVF with PGT and these days they tell you about carrier screening super early and everything here in California. I wouldn’t experiment on a real-life living human like this.
A last ditch effort to save a life perhaps but come on, dude.
If you're interested in the actual process of PGT and IVF, I wrote it down here: https://wiki.roshangeorge.dev/w/IVF
Well-trodden ground and quite safe.
Here's the key quote:
> The tradeoff is pretty straightforward: the US system emphasizes uniform standards and upfront rigor, while China’s [investigator-initiated trial] model pushes decision-making closer to the doctor and the patient, making it easier to start trials quickly and iterate as data comes in
It's clear that they are prioritizing iteration over standardization - which is a good pathway to exploration but will yield results like this. In the end, we're all going to benefit from the new research coming out of China as they subject themselves to this high-variance policy.
It's quite tragic that they felt the need to lean into this treatment and quite tragic that they were led on. Just a sad story all around.
Zack-D films tier writing there, disgusting.
questions of a layman - couldn't they initially do a small infusion of the [may be even weakened version of that] viruses to check for the immune reaction? May be such infusion would really serve as a vaccine prepping the immune system for the main infusion later? - though immune system killing the viruses may be nullifying the treatment - then may be when doing such therapy the patient needs to be [somewhat] immunosuppressed similar to transplant situations?
That's a problem for some types of RNA/DNA vaccines where they use a virus as a vector. You can usually only use a specific kind of virus once per patient.
This isn't the correct takeaway. AAV are one of the most complex drug modalities and carry considerable risk when used incorrectly. This story is tragic and violates pretty much every ethical consideration for a clinician researcher. Especially ones that are treating children of desperate parents.
That said, AAV are one of the most powerful delivery mechanism we have to deliver gene therapies to the brain. Uniqure has shown the first efficiacious treatment of Huntington's disease with intraparenchymal delivery of AAV5, Zolgensma is a brain targeted AAV9 to treat SMA, Kebilidi is an intraparenchymal AAV2 that treats AADC deficiency.
The general approach should be to keep dose as low as possible and minimally expose the periphery. AAV9 at large doses delivered intrathecally without standardized immunosuppression is simply insane.
The lesson for me is that you must advocate for yourself and your loved ones in the medical system, because doctors will not do it for you; they may not even perform the most basic risk assessments. And you have to try to quantify risk yourself, because doctors will refuse to give you the slightest hint of any number attached to risk (I know, I've tried many times).
The fair possibility is that it would be not the best choice for the patient,
But other possibility could be a schedule problem with the doctor holidays for example.
Or that it would be too expensive for the hospital
Or that they didn't have the materials or the experience
To go forward with this operations the interests of the patient, the doctor and the hospital must match. Sometimes only two parts benefit from it.
>will refuse to give you the slightest hint of any number attached to risk (I know, I've tried many times).
reminds me of my lawyer... (I lost)
I'm not passing judgment on the parents, I'm just pointing out that how society treats developmental delays is extremely important to the quality of life of these people.
Here in the US autism was considered a "mental illness" until the 1980's.
What's particularly galling is the recovery from back surgery would've taken at least 6-9 months of rehab and my father's PSP was already sapping his motor skills and yet the surgeon was pushing ahead.
Even with my mom I've had to intervene on several occasions against the doctor's utterly idiotic ideas. Thank goodness for AI to at least make us conversant to ask the right questions of these doctors.
It's like a teacher saying if you get caught cheating during the exam you will be punished, but if it's after you can get "scott-free."