Saving Lydia
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The problem with some mutations like this, is that they have an effect on the development of the brain from the start of the development and that fixing the gene (or better its RNA transscription) will not undo that development. The results of IQ tests seems to indicate that with my sons mutation, there is a problem with the myelination in his brain. Myeliniation is a process that starts before birth and continues into adolescent. At the moment he is quite happy and functioning well within his limits. His 'academic' IQ is rather low, but in some areas, he surpases the average person by far. He has a great sense of humor and people like him. In his case, I am really afraid what would happen if we would administer him a drug that would compensate for the genetic defect. Would he go through another fase of brain development and having to cope with all kinds of changes. Could he end up being less happy, because it would remove his ignorance about certain things. For example, at the moment he has no desire for a romantic relationship, but getting such a desire and than still not being able to satisfy it, could make him very unhappy.
My firstborn son has a genetic disorder and a long list of issues. I figured I had until he was about five or so to do anything meaningful about it. This turned out to not be true. The window for intervention was much longer.
He's 32 and much more functional than I ever expected him to be, though he still lives with me for now.
He still has zero interest in a romantic relationship. He and I have the same genetic disorder. I do not share his general lack of interest in romantic relationships.
I will suggest you try to not automatically lump in all of your child's characteristics with this one detail that he has a mutation. You might read up a bit on "ace" or "aromantic" people. There are people who just aren't terribly interested in romance. It's really not some bizarre defect.
I did see your other comment. I did understand that this was new and apparently unique.
I think about this a lot and don't have good answers. All I can say is that I have 3 goals for my daughter - and she doesn't need to be a 100% normal child to achieve any of those goals. 1) I hope my child is not in pain 2) I hope my child feels loved 3) I hope my child can find beauty in the world.
So, your example of the happiness / awareness tradeoff really applies to everyone. It probably applies to ancient myths like Adam+Eve, Prometheus etc. too. From history it is clear that seeking awareness at the risk of existential discomfort is something that people do.
Having said all that, this is an incredibly tough decision to make and is solely up to your family.
just fyi this is actually an active research topic, c.f. https://en.wikipedia.org/wiki/Oogonial_stem_cells#Research
The poor motor function is probably related to poor myelination of the nerves in his body, as his proprioception and pain perception are affected.
That we know of. There may be many more who were, say, born in a developing country and simply died without ever being identified as having this issue.
I generally agree with the impetus here to find some way to generalize treatment for "orphan" diseases so that more people have some hope of effective treatment. I have no idea if this particular approach will yield any real benefits.
Orphan disease: A disease that has not been adopted by the pharmaceutical industry because it provides little financial incentive for the private sector to make and market new medications to treat or prevent it. An orphan disease may be a rare disease (according to US criteria, a disease that affects fewer than 200,000 people) or a common disease that has been ignored (such as tuberculosis, cholera, typhoid, and malaria) because it is far more prevalent in developing countries than in the developed world.
Source (I don't recommend actually clicking on it. It had at least two pop-ups.):
https://www.medicinenet.com/script/main/art.asp?articlekey=1...
Shouldn't this be viewed more at the pathway level than at the base-pair level? Pathways have redundancies, and medicine can address a pathway. Focusing on base-pairs seems like a race you can't win, unless we have the technology that can reliably fix single nucleotide mutations.
The first technology is the production and delivery of messenger RNA made synthetically, and the second is the fusion of the recognition portion of CRISPR with a class of enzymes known as base editors.
Of course we'll have to start with the liver and with diseases that move the needle (i.e., not N of 1), but once the technology is approved in this case things get a lot more interesting for other genetic diseases that don't move the needle. Tim Yu developing the ASO for Mila is the perfect example of how once the technology is working for a money-making indication, less profitable treatments can follow.
If you want to read more about this, check out Beam Therapeutics, Moderna Therapeutics, Intellia Therapeutics, CRISPR Therapeutics, Editas, STRAND Therapeutics, Translate.bio, BioNTech, Josh Rosenthal at Woods Hole, Feng Zheng at MIT/Broad, and David Liu at Harvard.
I have nothing but sympathy for everyone involved and admiration for the strength of the parents. Few people are more motivated and capable than parents being told that a problem that affects their children cannot be solved.
Or does the medicine supplement the role of whatever that cell is supposed to do? (Assuming this affects some specific roles cells)
https://women.texaschildrens.org/program/high-risk-pregnancy...
Could it be that we identify a way to improve the genetic machinery itself, so that replication errors are less likely. or maybe a way to maintain DNA already in place in an individual (be it that the individual is born with it or gets it later, like cancer)
I mean publishing the hardware for a high-performance liquid chromatography, possibly 3D printed and the controlling software?
And the platform would produce the desired antisense oligonucleotides from an easy UI, like just describing the desired mutation, and the software would deal with the details?
I wonder how many people are living a miserable lives, without knowing they can b e treated. Do I have to Ph.D in every medical science to make sure my kids get a treatment what they deserve?
I mean there are 3 people (as far as they know) with this specific mutation. Time, money, and capable scientists are limited. Allocating these resources efficiently means that the more rare disease don't get as much attention, but this also means that you're saving more people. Just not those with the rare conditions.
From the article
> The rare label is wrong and limits progress. These are not rare. These are genetic and have the same root cause. We need a systematic, platform-driven approach to fix these typos. We need a spell check.
Yes, there are millions with some mutation. But changing around mutations needs to go through some form of medical process to see if it's safe. The current processes are there because historically there has been a lot of abuse for profit. We can't just platform allow any genetic editing. Some of these edits might be dangerous.
While you're correct that an individual treatment using this approach can never be tested against thousands of patients to determine safety (as it might only be needed by 3 people), it's either try it or watch thousands of people die.
The amount of work that goes into making sure that any single treatment isn't going to have unknown side effects is non-trivial. Just because there is a common toolkit doesn't make this safety testing go away. It automates the design of the safety tests somewhat, but doesn't make them any less important. This means that for every... single... anti-sense oligo that's designed, there needs to be significant testing done to make sure that it does what is expected and doesn't have any adverse side effects.
In many cases, it's the first part -- the design of the treatment -- that is rate limiting. The benefit of something like these N-of-1 ASO trials is that you're streamlining the first step in the process. But that doesn't mean you can just skip the other steps. And yes, these steps are expensive.
I do agree that this is something worth following. If it's really provable that this platform solution is universally safe, that's amazing. But that doesn't mean the system is broken. Just that until now, this was probably not the proverbial low-hanging fruit of medicine, even with a million people there are diseases affecting billions. It may still be worth more investing in those disease that affect billions.
>it's either try it or watch thousands of people die.
How many of these genetic diseases are deadly? A lot of these mutations may be bad but not deadly. If now the treatment is universally approved and kills some people, think about who's going to take the responsibility for it?
Same as any other medical intervention. A substantial number of people die as the result of routine surgery for problems that themselves weren't life-threatening. Medicine, like engineering, involves tradeoffs and risk assessment, and there is not likely to be a perfect outcome. All we can do is work on the "best" outcome for the most people.
Let me rephrase this less charitably: You are willing to rob millions of suffering people the chance of a cure, by mandating a system that effectively prevents a cure from being developed. This is in order to save some of the very same people from the effects of unsafe treatment. It is patently absurd, but that's exactly the system that we have right now. Nobody wants to take on the legal liability of killing a terminal cancer patient with an experimental treatment unless they have military-grade legal assistance at their disposal.
It's also clearly not working when countless desperate people opt for "alternative medicine" and various quackeries that aren't held to those standards, simply because they're not advertised as "medicine" in the legal sense.
If you've ever asked yourself why health care is so expensive in the US, don't overlook the safety standards and the legal liabilities that medical practitioners incur. Look at the value of settlements in US courts. Practitioners require expensive legal insurance, and they'll charge you for it.
The cure may be worse than the disease, I bet not every one of these one-off mutations is deadly, and how debilitating it is may vary. I'm not trying to rob anyone from the chance of a cure, I'm just saying that to save the most people, resource allocation makes sense.
Now if the incentives are misaligned by virtue of the laws we write, we might need to change those.
I wasn't arguing with resource allocation, I was arguing with your "safety concerns". My takeaway from the article is that with the current framework, any treatment needs to go through countless trials individually, hence it is literally impossible to do any trials to prove the safety or efficacy any treatment that is bespoke to a handful of people.
In our system, it's the responsibility of private companies to productize findings from research and development. As a result, resources aren't allocated to save the most people, they're allocated to make the most money. If you make it expensive to develop treatments for diseases, or you limit the profit that can be made from these treatments, those treatments will never be developed. No pharma company loses money just because people die. They lose money from dead people they could have treated at a profit.
> Now if the incentives are misaligned by virtue of the laws we write, we might need to change those.
The incentives are aligned towards not taking risks. You will not read a headline "Millions of people died as a result of overly strict safety standards". Even though that may very well be the case, it would just be a conjecture. On the other hand, if a handful of people die from some FDA-approved drug, it's all over the news, people will demand consequences, million-dollar lawsuits will be filed, and so on.
Texas did some malpractice law changes back in 2003. It would be interesting to see if in impact their health care costs.
1,000,000 * 100,000 = 100,000,000,000
A possible 100 Trillion dollar industry seems like a very stupid thing to ignore.
The other thing to remember is that making a genetic toolkit to fix genetic errors is a potentially low liability solution, if well tested, documented and proven. The liability would still rest primarily with the practitioner.
Even taking your optimistic numbers at face value, that's revenue, not profit. A 100 billion dollar industry with what I would conservatively estimate as having several trillion in costs is not something we can pursue.
I've got my own boutique genetic problems in my house (not quite a one-off in effect, but probably technically novel), so I've got skin in the game, but this is just wishful thinking. Even just funding all the known rare diseases is not something we can really afford, let alone dedicating millions to every one-off mutation. We aren't that rich.
I'm sympathetic to claims we ought to have enough for food and water and basic housing for everybody, but that does not translate into having enough to create custom bespoke medical research programs for everybody, or even a significant fraction of "everybody". If nothing else, food, water, and basic housing are widespread skills; fixing genetic errors would always bottleneck on the number of available people who can do it, which is never going to be as large as the number of people who can build some sort of house.
Both countries with socialized medicine and yet they still didn't come up with a cure. It happened in one of the most, if not the most, capitalistic tech-hubs in the world. Maybe there's just something about the private sector that gets things done.
This is misleading. The original post was about medical research, which neither in Greece nor in England is any more "socialized" than elsewhere. They might have national health services, but those buy their medicines from the same private actors as any hospital in the United States.
Also note that the original article is specifically not about profit-driven R&D but about a donation-funded, non-profit venture. The (hopeful!) success of such a venture does not really translate well into an argument for private, for-profit medicine R&D.
You could argue that it's the raw capitalistic drive of SV that is uniquely able to generate the wealth necessary for such non-profit ventures, ok, fine (there are also counter arguments to this), but this was not really the point of the original comment.
A lot of the big medical innovations still come from the private sector. The question is only whether we can get the interests aligned here.
The doctors they went to wrote things off and sent them on their way multiple times, but they reached out to close friends for recommendations on second opinions because they still didn’t feel right. Doctor A tells Doctor B to do him a favor and take a closer look, and lo and behold, emergency surgery saved their life.
We’re obviously talking upper middle class people with great insurance. The system is very broken.
We live in an age where so much stuff is so readily fixable we don't remember how common this used to be.
We keep eliminating sources of error, but there will always be a long tail of small-scale mistakes with large-scale consequences
When you live in a society you have duties and rights. We count on each other. Some people gets an education with help and resources of society and then there is an expectation for them to take responsibility and do their part. That is expected from everybody whatever your role, studies or background.
You are right that this social contract seems broken. That we are told that everyone is on their own and if you don't profit as much as possible from the system you are a sucker. That cheaters are right. This doesn't work on the long run. Too much cheaters in a society and it is doomed to fail.
We should take care of ourselves and others. We have rights and we should be willing to fulfill our duties. And have expectations on others to do the same.
When you have finite resources you have to ask whether its worth spending those resources on something that can help 1 person or a million.
Not necessarily. What are you doing to contribute?
I find most people work this way. A few are true saints, a few are pure evil, the rest are selfish with varying degrees of outcome.
One could even say that the resources spent on saving this baby could be better spent on saving far more others, and that prioritizing a single person over a group is a selfish action.
So are you really doing the best you can do?
Nope, that is not what you are doing.
Sometimes when I see titles like this, it is better to just get to the point rather than confuse readers with these silly titles. Apart from that, it was a very good read.
It's a new approach. There's a serious language issue here in that truly new things don't really have proper words or phrases for them yet. They need to be invented.
That's usually done by initially borrowing on existing concepts that are as similar in some way as possible.
This problem space also seems particularly thorny. Even people who have genetic disorders -- or who have a child with a genetic disorder -- may not understand some basics about how genetics works.
Over the next few months, we will start by asking our
collaborators to open source everything from Lydia’s
N-of-1— the process, costs, contracts, protocols,
assays, cell lines and data.The only bit that seems like open source is "anyone performing an N-of-1 should be able to tap into this repository as long as they contribute back into it", which implies a share-alike kind of license. Not sure how copyrightable this type of thing is though, so it might be just reliant on good will.
I think the title is total clickbait and not what's happening at all.
If they licensed their Baby's DNA under some open source license then maybe we could say that they were open sourcing their baby, but:
- Don't think that is what they were doing.
- Not sure they own the copyright of their baby's DNA.
- Don't think that would be legal to do.
It isn't a journalistic article and so the writer should be forgiven for using a touch of their creativity with the title. Had this been from a news organization I would probably feel rather differently.
Even in that ridiculous analogy, that's sharing binaries with the source kept closed!
And except for intellectual property issues, I don't see a problem with publishing treatment details, either.
There are some issues about providing medical advice without license, but that can be circumvented with a few disclaimers.
I know it's an HN tradition, but empathy is important, friend.
Other has no positive benefits, while it can be dangerous to the child.
Kickstarter tawdriness is creeping into what was otherwise a gold-plated medical GoFundMe.
Before sharing more publicly, we decided to update to the actual amount and had also learned that some costs would be higher than expected (toxicology package would be higher, clinical care wasn't going to be covered by insurance etc.). We had put a little note describing this in the FAQ, but I understand that no one reads those.
For what it's worth, our goal from the very start was to openly share the process and logistics because we are truly convinced that this N-of-1 process can be repeated quite easily. Perhaps, at the very least we can squeeze the time for the next motivated parent to learn all this from 6 months to 1 months.
Currently it is structured to make-pill-mint-money for drug companies. If a disease/treatment isn't mass produced, THEY DON'T CARE.
Medical devices are a bit closer to what is needed, but fundamentally they are run by the same business models.
Instead what will probably be required is a lot of specific testing (labor intensive), computational analysis (some labor and analysis) that produces the necessary treatment formula (or CRISPR design, etc), and then something that produces it.
The margins won't be great, so no MBA-driven healthcare will care about that.
The biggest disease that needs this approach to approach a "cure": CANCER. Cancer, even the "common" ones, are the result of dozens of varieties/combinations of gene malfunctions.
First world nations should pool money to start a multinational infrastructure that includes continuous improvement. Sections of this can probably be make profitable, but those will probably be lots of small companies.
All of which would be GREAT for employment.
There's plenty of serious health issues constantly competing for a small pool of smart medical peoples attention and with a limited capital.
Genetic tailoring still currently involves a high amount of specialist attention per individual and there is plenty of research and money going into it. I've heard multiple doctors tell me it's the future of medicine.
Whether it could use more attention and capital is certainly a good question.