It’s good news, but it doesn’t mean that there still aren’t more challenges to overcome.
I think the article ends on a really important note:
“The increasing cost of manufacturing these treatments makes it extremely difficult, if not impossible, to develop and test gene therapy for many ultrarare diseases where the number of patients worldwide is very small and profitability low.
We were able to deliver these treatments to the children in our ongoing clinical trials thanks only to funding from a generous family whose own child is a participant”
I'm not an expert, but I've started a biomedical science degree, and - struggling for the right word here - the 'systemisation' of the tools for genetic engineering is astonishing. There's a revolution happening here, not just in the cutting edge tools, but also in the streamlining and automation of workflow, I find it hard to believe custom genetic treatments are going to stay expensive for long
These vectors contain a number of indicator genes, such as antibiotic resistance, so you can use the antibiotic to kill the bacteria that didn't take up your vector.
The vectors have a prepared insertion site to take your gene, that's right in the middle of another gene that produces a colored product.
If the your resultant bacteria produces the colored product, you know you gene didn't make it into the insertion site or it would have broken that gene.
There's vast catalogues of this stuff.
Then when you want to do full genetic sequence to see where your gene has inserted, that's pretty much automated for you.
If your experience is anything like mine, once you start searching for this, google ads is going to lure you into the rabbit hole with offers to 'automate your agrigenomic high throughput whole sequence workflow' and 'rapid de novo genome assembly'
Some of the stuff google is trying to sell me, seems only slightly more non-fictional than 'mystery flesh pit national park', which is of course a searchable phrase.
This is what I was hoping to hear, commoditizing all of the tools would be a huge benefit, I guess on the flip side is could make bioengineering of deadly things easier?
Many exciting new biotechnologies are incredibly expensive like gene therapy, T cell therapy, or some other radical life-saving therapy. Regulations are one factor driving up costs, as well as the manufacturing costs. It is not easy and really annoying when people think it is overpriced
When you compare such to current costs of conventional treatment, it's often not that bad. That's before you factor in pain, suffering and lost productivity of the patient and their caregivers.
The problem is figuring out how to pay for such things to begin with.
It was posed to be a revolution when I started my career, some 30 or so years ago. The pace is glacial. There is no systematic way to deal with this; nearly every disease has its own details, and individuals differ so many treatments have to be personalized. Many of the changes we make, we don't really know how or why they work.
I've left human biology and returned to model organisms because the experiments allow for much less ambiguity.
Yeah it seems like that was the norm in the past, but it’s looking like CRISPR and it’s successors are shaped to change that. As long as the set of relevant genes is small, and in a small enough number of cells it should be possible to scale up. Genetic degenerative diseases of the eye, sickle cell, and similar show a lot of promise.
> Everyone who tried it thought they were doing their victims a favor.
No, not everyone who did it thought that they were doing their victims a favor. Quite a lot saw their victims as people who ought to be sacrificed for the good of others, and if they thought they were doing them a favor it was only in not murdering them outright as well as preventing them from reproducing.
Of course, some eugenics practitioners didn't bother avoiding outright murder, e.g., the Nazis.
This is a bit of a tangent off me pointing out someone's suggestion was eugenics. I'm not sure what I'm supposed to take away from this comment. We obviously can't read the minds of eugenics pushers, and very few openly admit their True Aims, so there's not any point trying to litigate it here.
Not just Israel - most Jews everywhere will use the screening. If two people are both carriers they suggest they don't marry, normally the screening is checked after the first date.
And regarding eugenics they only screen for diseases that require two carriers, because such a person can marry someone who is not a carrier. Diseases that manifest with a single copy of the gene are specifically not screened for because there's nothing the person can do in that case.
Apologies then just your reply seemed to indicate that you were agreeing with these screenings and the termination that follows them being eugenics.
My litmus test for eugenics requires an ideological and social engineering component.
Simply telling parents well if you bring a child to the world they’ll die within 2 years and suffer greatly isn’t that. Neither is offering them other tools such as using a sperm or egg donor or adoption.
The OP to which I declined to reply says: No one should be born with Tay-Sachs, a genetic disease.
I agreed with a reply to that suggesting such an extreme and unnuanced statement amounted to eugenics since the only means to actually ensure that no child will ever be born with X genetic disease would require rather extreme measures that go far beyond providing testing and options.
> Just calling every genetic screening designed to prevent actual suffering eugenics is pretty nonsensical.
It’s also not wrong, if we’re being totally honest.
Things are either eu (beneficial) or dys (harmful) genic.
The bottom 75% of the IQ curve has been poisoned against the word “eugenics” to the point that they can’t even have a basic conversation about things as sane as “genetic screening for debilitating illness” without completely breaking down.
The bottom 75% of the IQ curve has been poisoned against the word “eugenics” to the point that they can’t even have a basic conversation about things as sane as “genetic screening for debilitating illness” without completely breaking down.
This is a really not good way to engage with this topic. I'm not happy seeing this kind of framing on HN of what is an extremely sensitive topic for many people and with good reason.
Agreed. I think some people in the pro-eugenics crowd mistake a broad anti-eugenics stance as an ignorant denial of possible benefits. I think it could be good and fine, but I don't trust humans to make those decisions. I don't trust myself to make that call.
I don't think there's any real venue in which a discussion of permanent germline modification of humanity (or in-utero modification that affects all cells) can be rationally discussed. I've never seen any productive discussion of this in any context. It's one of the few issues that dives so deeply to the core of the human value system that it's truly challenging to come up even with the terms of the debate.
That said I expect that in the future, for many genetically inherited diseases, parents will be given the option to address the problem without termination, so long as the solution seems to be exceptionally safe and highly effective (IE, 99.999% confidence the outcome will be positive). I don't think people will see that as "eugenics", although there have been a few press campaigns that have done so.
I had no idea. I just used my "wait, no, that's eugenics" heuristic. Now I know!
One day it's "we should save these kids from a difficult life," the next it's "we need symbols to tell undesirables apart," the next it's "we have too many people in camps and nowhere to send them." People like me ended up in those camps next to the Jews, so I'm not keen on the noise that starts the landslide.
There's an unfortunate truth that proponents of equality are going to have to deal with at some point: we are biologically different, to greater or lesser degrees.
That's a fact. And it's only going to be more of a fact the deeper we dig into our genetic code.
But it's how we respond to and deal with that that determines whether we commit good or evil.
1. Tay-Sachs is not limited to a single ethnicity. Carriers exist in the population in general.
2. Assuming you’re referring to the fact that being a carrier is more common in Ashkenazi Jews, you’re aware that there are a number of genetic screening programs run by Jewish organizations, right?
Dude, there are people who have children with Tay-Sachs, who are NOT ethnically Jewish at all. 1 in 250 people in the general population is a carrier for Tay-Sachs.
Also, literally everyone is a carrier of mutations for extremely devastating diseases. You just do not know which ones.
“While anyone can be a carrier of Tay-Sachs, the incidence of the disease is significantly higher among people of eastern European (Ashkenazi) Jewish descent. Approximately one in every 27 Jews in the United States is a carrier of the Tay-Sachs disease gene. Non-Jewish French Canadians living near the St. Lawrence River and in the Cajun community of Louisiana also have a higher incidence of Tay-Sachs. For the general population, about one in 250 people are carriers.”
I don't understand, the parent said nothing about Jews at all. Nonetheless, given the incidence among them, they also happen to be pioneers in prescreening for this very genetic defect.
Yeah, that's weird. Either the association is so strong with some people that they can't see Tay-Sachs without immediately thinking Ashkenazi, or there was a stealth edit to the comment.
Not all cases are detected. Unfortunately, rare mutations are missed by panels used in the United States.
This person, who has no Jewish ancestry whatsoever, has a Jewish husband. They got tested for Tay-Sachs using a standard panel in the United States. Their rare mutation for Tay-Sachs got missed and their child had it. :-(
"Rapp was shocked. During her pregnancy she had been tested twice for Tay-Sachs, and both times the test came back negative. She later learned that a standard Tay-Sachs screening covers only the nine most common mutations. Rapp, who is not Jewish, and her husband, who is, were carriers of a rare mutation. To put this in perspective, fewer than 20 children in the United States are born each year with Tay-Sachs to parents who, like Rapp, tested negative and thought they could cross that worry off their lists."
They did everything right.
As I said before, there are also other cases where parents are NOT Jewish at all, and end up having a kid with Tay-Sachs.
Not all parents have the resources to do these genetic tests, and insurance, in the generally speaking, does not cover such testing for genetic diseases such as Tay-Sachs in the United States.
"Despite position statements from the American College of Obstetricians and Gynecologists (ACOG) stating it is a basic standard of care to screen persons of French-Canadian, Louisiana-Cajun and Ashkenazi Jewish descent for Tay-Sachs, some may have issues with getting coverage for carrier screening. NTSAD can help you appeal for coverage and at the same time educate the healthcare industry about the importance of genetic testing prior to conception.
If you are having problems with insurance covering your carrier test, please contact the office at (617) 277-4463 or info@ntsad.org for assistance with the appeal. We will need your name, address and plan number. The office will provide a letter of support to your insurance company as well as educational materials to present to their medical review team.
It is important to note that while the appeal process and potential out-of-pocket cost of genetic testing may seem daunting, it is a drop in the bucket compared to caring for a child affected by Tay-Sachs, Canavan or another allied disease."
You're right, but socially and organizationally it's more practical to fix the problem via gene therapy rather than institute compulsory abortions after a genetic test. Unfortunately due to the barbarity of Nazi Germany even rational eugenics programs are taboo in the West, and trying to fight that is a losing battle.
Um, US has its own sad history of eugenics (predating Nazi germany) that was unfortunately tied very closely to the mainstream scientific establishment.
https://www.cshl.edu/archives/institutional-collections/euge...
This included advocating for "sterilization of defectives".
And of course we mustn't forget the reaction to He Jiankui, who claims to have created the first permanently modified humans, and the response in China was to jail him and fine him. It's not just the West.
Gene therapy done in a medical setting where society has had a chance to understand what's going on isn't really eugenics, or is a form that isn't "bad". It's different from "sterilize the defectives" and "X people are Yer then Z people", especially because the people doing this have consulted extensively with bioethical experts and have also subjected their plans to scrutiny by the larger society.
Voluntary screening of prospective parents for genetic disorders doesn’t seem malicious to me. Especially if they already know they are at high risk. If my partner and I realized we would have a child with an inherited burden, we’d probably adopt instead.
You could say this counts as Eugenics, but maybe people just need a different word since Eugenics is so tainted.
Then you get into more difficult discussions. Like what constitutes a "inherited burden? Down syndrome? Is it okay to develop policies where few to no people with down syndrome will exist? How about autism? Can we get rid of people who might be liable to get depression, or just be really short? There is so much to screening for genetics, and not simply because the word eugenics is tainted.
I'd leave these questions to the biomedical community, as they have the ability to deal with nuanced questions like this. Given the amount of different behavior covered by autism, it doesn't seem useful to use that as an example.
I think if there was a test for Down's syndrome and a gene therapy cure, that would almost certainly be deployed, and advocates for people with Down's aren't going to have a big problem with that. People learned from the autism speaks debacle.
"The increasing cost of manufacturing these treatments makes it extremely difficult, if not impossible, to develop and test gene therapy for many ultrarare diseases where the number of patients worldwide is very small and profitability low.
We were able to deliver these treatments to the children in our ongoing clinical trials thanks only to funding from a generous family whose own child is a participant. This grassroots approach is a common theme in ultrarare disease research – development and testing are often supported by parents, foundations and federal grants."
FYI - if anyone here is interested in helping these kinds of causes, a company called Orchard Therapeutics provides similar treatments and has just signed a historic agreement for reimbursement for treating MLD patients in Europe (you can read more about it here: https://www.globenewswire.com/news-release/2022/02/04/237899...).
Also big discretion: I do have a lot invested in the company and I have incurred significant losses since deciding to invest in it. In the brilliant world of pyramid schemes vested around crypto-coins and NFTs, I don't regret anything and will keep buying more shares to support the dignity of human life.
>We were able to deliver these treatments to the children in our ongoing clinical trials thanks only to funding from a generous family whose own child is a participant.
We probably shouldn't put the main focus on rare disease but on genetic manipulation in general. It would be much more valuable to be able to cure arbitrary genetic defects than just the ones that are somewhere between uncommon and extant.
I mean, this has definitely happened in the past; study of various rare genetic diseases has elucidated and illuminated the processes by which diseases occur at a molecular level, and often have utility far outside the original rare disease.
As to whether that means it's an effective payoff if you put more money in rare diseases (and therefore less into non-rare diseases), I can't say, so instead, I have a portfolio with a small but not tiny amount for the collection of all rare diseases.
It's weird to say 'only' since I assume that a lot more went into this effort other than funding. There are a lot of initiatives that have a lot of funding, but little success. Either way, this result is certainly better than nothing, or waiting years/decades for public funding.
'Only' implies that the funding was necessary, not that the funding was fully responsible. Also consider that 'only' was said by the researchers. From their pov the effort is a given, because that is what they control, while the funding is an anomalous outside factor.
It’s just tough because resources are not unlimited. You’ll save many more lives focusing on new antibiotics and then you will on Tay-Sachs. I don’t think there’s enough researchers in the world to focus on every single rare disease.
I don't have anything to add except that for some reason, I viscerally remember the first time I heard of Tay-Sachs disease in a high school classroom through a video about genetics.
Something made me feel so disturbed about this one disease above all else because of the seeming hopelessness of the situation coupled with the rampant cruelty of how it kills kids from the inside and seemingly reverses developmental progress.
I don't know why I just remember the moment I learned about this, but this is great news. Hopefully this is the first in many such therapies.
I was a little surprised that the researcher talked only about stopping disease progression, rather than reversal.
Especially for the 7-month old.
I assumed that at that age, the brain was still growing / adapting in ways that could work around the earlier problems.
But now that I think about it, I've heard that oxygen deprivation during birth can cause permanent impairment.
For genetic conditions like this one, it's typically a positive feedback loop -- aka vicious cycle -- where the sicker they get, the sicker they get and it accelerates.
Stopping the normal progression would be a huge win in its own right.
Reading the article, I'm not seeing much info on how the results were 7 months old in terms of brain development. At that age, one would expect brain development to improve. I hope the researchers discuss this in more detail in future news.
This is actually the 2nd brain gene therapy research I've seen.
In the Phase I trial below, injecting telomerase and klotho AV vectors into CNS/brain was safe and it improved cognitive scores of 5 dementia patients after 1 yr follow up.
This space will hopefully get very big. Mice lifespans were extended 25-40% (massive!) through similar techniques. See Dr George Church Gene Therapy for more.
I was actually thinking about Tay-Sachs this morning on a walk, after I passed by a church with a billboard out front that says "Christ died for all, even babies in the womb".
I learned about Tay-Sachs in high school biology. I think we watched a short documentary on it, as an example of genetic inheritance, and the importance of enzyme function. I remember being so surprised that something so simple (absence of one protein) could be so horrible. A beyond-grim prognosis, and immeasurable/unavoidable suffering for everyone involved. Since then, it's been something that I can't reconcile with the existence of a higher benevolent being. I'm no expert, but it made a lasting impression on me.
I'm so uplifted that researchers have made progress on curing this senseless disease.
I don’t think GP is questioning whether those dying infants’ lives were valuable. I think their point is, those lives were valuable, so how could a benevolent, all-powerful creature allow them to suffer and die merely due to a genetic bug.
If you're interested in learning more, the book Code Breaker is a great background to some of the steps that were taken to get us to where we are today! This work has been decades in the making :)
"""
I am a member of a team of researchers from UMass Chan Medical School and Auburn University who developed a gene therapy that may help get around this barrier. Our treatment uses two harmless viral vectors to deliver DNA instructions to brain cells that teach them how to produce the missing enzyme. Similar techniques have been used to treat a number of related diseases and other conditions. In the case of Tay-Sachs, these DNA instructions enter the nucleus of these cells and stay there, allowing for long-term production of HexA.
"""
They use a monkey virus to deliver two mRNA codes to brain cells, the mRNA after being transcribed, tells the brain cells to create HexA to deal with the target enzyme.
Okay, I get that much.
But how on earth does this work.
"""
these DNA instructions enter the nucleus of these cells and stay there
"""
I thought mRNA could not alter DNA and it was by definition broken down after use by the cell, ie short term by definition?
Plenty of viruses use DNA and not RNA. The virus injects it's DNA sequence into the host DNA.
This is why people have "flare ups" of herpes/cold sores. That is a DNA virus, so once the cells are infected they carry that DNA sequence forever, even after the cells divide.
Gene therapy is the game-changer which will enable us to eventually cure cancer. I've been proposing that government stop all investment in refining non-gene therapies, such as radiation and chemotherapy, and to plow everything we have into gene-therapy.
Cancer is essentially a genetic disease and we can solve it by repairing the faulty genes, just as with Tay Disease.
But these 2 kids are a lot healthier than than they would have been without this incredible invention. This is the kind of stuff we can hold on to.
Thanks for sharing.