»Mr. Klein wants to keep control over bad stories.«
July 20, 2016 7:34 AM Subscribe
Christoph Klein, director of the Dr. von Hauner Children's Hospital in Munich, is considered an excellent doctor with plenty of ambition. Too much? For years, Klein has been pursuing an experimental study. Several of the children he has treated are now dead.
On 22 April 2016, Süddeutsche Zeitung Magazin (a weekly supplement to the German daily newspaper Süddeutsche Zeitung (previously)) ran an 11 page story on a gene therapy research project by star pediatric oncologist Christoph Klein (de:wiki) that would turn out to have serious consequences for the children involved.
Dr. Klein has taken legal action following the publication of the story. As a response SZ has made the article fully available free of charge in German and English.
Reminds me of the Paolo Macchiarini saga that's been going on in Sweden over the last year or so, where it took multiple investigative reports from different media outlets before his employer, Karolinska Institutet (of Nobel-prize fame) finally decided that maybe something wasn't quite right after all.
Not sure if there are any recent summaries of the medical situation in English, but this Vanity Fair story is crazy enough.
posted by effbot at 8:40 AM on July 20, 2016
Not sure if there are any recent summaries of the medical situation in English, but this Vanity Fair story is crazy enough.
posted by effbot at 8:40 AM on July 20, 2016
effbot - Retraction Watch have covered a lot of the developments about Macchiarini; this article summarises a lot, and if you check out their Macchiarini tag.
Fascinating link brokkr, thanks for posting it.
posted by Vortisaur at 11:51 AM on July 20, 2016 [1 favorite]
Fascinating link brokkr, thanks for posting it.
posted by Vortisaur at 11:51 AM on July 20, 2016 [1 favorite]
That is outstandingly careful, and thorough reporting; I can't think of an example first published in English to match it.
posted by jamjam at 12:45 PM on July 20, 2016
posted by jamjam at 12:45 PM on July 20, 2016
I'm somewhat confused about why the gene therapy caused leukemia. But that was such a good article, so clear and thorough.
posted by jeather at 12:57 PM on July 20, 2016
posted by jeather at 12:57 PM on July 20, 2016
This is an older article which explains the leukaemia in the French SCID study. They used a retroviral vector to get a fixed copy of the broken gene to insert itself into the genome of the stem cells, so that the cells derived from that cell would all have a fixed copy, but with those retroviruses they couldn't target where the fixed gene actually goes in the genome. If it goes into the wrong place, it can disrupt another gene which might be essential to proper cell division and growth, and that leads to leukaemia. Newer methods of gene therapy use more specific targeting methods so there is less chance of disrupting another gene.
posted by penguinliz at 2:30 PM on July 20, 2016 [2 favorites]
posted by penguinliz at 2:30 PM on July 20, 2016 [2 favorites]
I was bothered by this:
But the history of gene therapy is also a history of risk. It's impossible to remove its association with the name of Jesse Gelsinger, an American who died in 1999 just four days after undergoing gene therapy. The University of Pennsylvania had broken clinical research rules in treating the 18-year-old, who was not particularly sick compared with other patients suffering from the same illness as he. Gelsinger likely could have lived using a strict diet and good medicine. As it turned out, he wasn't just killed by his illness, but by the gene therapy treatment itself. Since that first death it's been clear: Gene therapy doesn't just offer hope.
There were some undisclosed issues in the trial in which Gelsinger died, but they had nothing to do with how sick he was. Most of the other participants in the study were asymptomatic carriers of the condition, many of whom were mothers of dead babies, whereas Gelsinger was an unusual case, a mosaic with an apparent spontaneous mutation, which caused him to have less severe symptoms. Gelsinger and the other participants were altruistic participants in a study of a treatment for terminally ill babies. Experimental treatment on those babies carries many more serious ethical risks than treatment of altruistic asymptomatic or less symptomatic adult volunteers. Suggesting otherwise is to me an insult to Jesse Gelsinger and his reason for participating.
posted by hydropsyche at 5:32 PM on July 20, 2016 [1 favorite]
But the history of gene therapy is also a history of risk. It's impossible to remove its association with the name of Jesse Gelsinger, an American who died in 1999 just four days after undergoing gene therapy. The University of Pennsylvania had broken clinical research rules in treating the 18-year-old, who was not particularly sick compared with other patients suffering from the same illness as he. Gelsinger likely could have lived using a strict diet and good medicine. As it turned out, he wasn't just killed by his illness, but by the gene therapy treatment itself. Since that first death it's been clear: Gene therapy doesn't just offer hope.
There were some undisclosed issues in the trial in which Gelsinger died, but they had nothing to do with how sick he was. Most of the other participants in the study were asymptomatic carriers of the condition, many of whom were mothers of dead babies, whereas Gelsinger was an unusual case, a mosaic with an apparent spontaneous mutation, which caused him to have less severe symptoms. Gelsinger and the other participants were altruistic participants in a study of a treatment for terminally ill babies. Experimental treatment on those babies carries many more serious ethical risks than treatment of altruistic asymptomatic or less symptomatic adult volunteers. Suggesting otherwise is to me an insult to Jesse Gelsinger and his reason for participating.
posted by hydropsyche at 5:32 PM on July 20, 2016 [1 favorite]
In other words, the patients in this study were duped. The doctors could have saved those children's lives, and they chose not to. That's heinous. Jesse was not duped. He knew he could manage his condition just fine, he had no illusion that this study would help him, but he wanted to save other children's lives. That's admirable.
posted by hydropsyche at 5:37 PM on July 20, 2016 [1 favorite]
posted by hydropsyche at 5:37 PM on July 20, 2016 [1 favorite]
This is really well researched and written piece. I work in this area, and the article covers topics that we spend a lot of time discussing. Very thought provoking.
The potential of the technology for a cure, particularly in rare fatal diseases, is enormous. But, clinical research at this stage is not without significant risk. I agree with the author it would have been much more appropriate to exclude participants who had a matched donor, especially given how new the approach was. There is a risk of graft-versus-host with autologous transplant, but that should be considered against the risks of the experimental therapy.
I'll do my best to answer the question above: I'm somewhat confused about why the gene therapy caused leukemia
The article calls the 'taxi' for the genetic information a vector, which is inserted into the patient's DNA. There are typically at least two passengers in the taxi: the gene of interest and something called a promoter, which increases how often the gene is used to make a new protein. With the types of 'taxis' that were being used in this case, the vector (including the promoter) was being inserted all over the patient's DNA. In some instances, the promoter was inserted next to another gene responsible for cell growth. For these patients, cell growth was increased and became uncontrolled, which led to the leukemia.
From a PubMed search, it looks like the culprit was LMO2, which was also led to problems in other retroviral-based gene therapy studies.
The field has moved beyond retroviruses, but newer approaches don't have full clinical validation and are not without risk either. The incredibly difficult part is to do the research in a way that is transparent and responsible.
posted by Otherwise at 6:44 PM on July 20, 2016 [5 favorites]
The potential of the technology for a cure, particularly in rare fatal diseases, is enormous. But, clinical research at this stage is not without significant risk. I agree with the author it would have been much more appropriate to exclude participants who had a matched donor, especially given how new the approach was. There is a risk of graft-versus-host with autologous transplant, but that should be considered against the risks of the experimental therapy.
I'll do my best to answer the question above: I'm somewhat confused about why the gene therapy caused leukemia
The article calls the 'taxi' for the genetic information a vector, which is inserted into the patient's DNA. There are typically at least two passengers in the taxi: the gene of interest and something called a promoter, which increases how often the gene is used to make a new protein. With the types of 'taxis' that were being used in this case, the vector (including the promoter) was being inserted all over the patient's DNA. In some instances, the promoter was inserted next to another gene responsible for cell growth. For these patients, cell growth was increased and became uncontrolled, which led to the leukemia.
From a PubMed search, it looks like the culprit was LMO2, which was also led to problems in other retroviral-based gene therapy studies.
The field has moved beyond retroviruses, but newer approaches don't have full clinical validation and are not without risk either. The incredibly difficult part is to do the research in a way that is transparent and responsible.
posted by Otherwise at 6:44 PM on July 20, 2016 [5 favorites]
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Thanks for posting!
posted by telepanda at 8:15 AM on July 20, 2016 [5 favorites]