Saving Lydia

https://medium.com/lydian-accelerator/saving-lydia-62a1c0bdf0fb

by dsr12 • 7 years ago

639 110 7 years ago

amelius• 7 years ago

This is a classic long tail problem — no mutation is common enough, but collectively there are tons. The existing Pharma approach to treat these is broken — they look for common typos and fix them with long drawn out trials. This barely makes a dent. Worse, they have put each in its own bucket and labeled them as rare, so the majority of the world feels they‘re not important to fix.

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.

DrAwdeOccarim• 7 years ago

That's the super exciting and interesting part of literally today. There are two new technologies that are about to combine that will probably get us to "reliably fix single nucleotide mutations." in a platform sense within the next 5 years.

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.

fjfaase5• 7 years ago

My son too has a unique and disabling mutation. As far as I know, he is the only person with this mutation, but there are more people with a mutation in the same region of the gene, that are affected in the same way.

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.

tapland• 7 years ago

I have one as well that is herideraty but no relatives have it (tested after finding out I had it). I think it's usually something like 1 in 400k people having a mutation of a specific gene.

fjfaase5• 7 years ago

De novo mutations (DNM), that is new mutations, is rather high and increases stronly with the age of the father, because sperm cells are produced by continued cell divisions, where the egg cells of women are produced before birth. With the mother there is also a slight increase over time, but the number of even old mothers is lower than that of young fathers. Luckily, only a small part of the DNM occur in genes and some mutations are not even harmfull, due to how triplets of base pairs are decoded into amino-acids. And then there are also many mutations that do have an effect on the protein being produced, but that the difference does not have a great effect. For most genes there are many variants, which all leads to working proteins, some of which might work slightly better than others in some area and maybe (slightly) better in another area. (Just recently there was a news item about how humans lack a certain gene compared to other mamals, which increases our risk with respect to cardiovascular disease, but apparently also increases our ability to walk/run long distances.)

air7• 7 years ago

That's a very powerful point. Every treatment (nay everything) is a one-way door: You do something, and there's no going back. With general medicine you can at least infer some knowledge based on other people's reaction to the same drug. But in "N-of-1" drugs, you're left completely in the dark. It's (going to be) a very hard call to make.

sslapec• 7 years ago

Flowers for Algernon by Daniel Keyes is exactly about this topic.

jpittis• 7 years ago

I interpreted it more as a story about aging. I guess both!

mhb• 7 years ago

As is Asimov's The Secret Sense: https://archive.org/details/TheSecretSense

radicalbyte2• 7 years ago

Beat me to it. Fantastic book.

DoreenMichele4• 7 years ago

If you know the specific issue -- the pathway the problem follows -- you may be able to do something about it more gently than some big irreversible drug.

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.

fjfaase5• 7 years ago

To clarify, the mutation of my son is not inherited, it is a new mutation, which most likely occured in my sperm cells. Not having an interest in romance is but one of the least symptoms he has. I only took it as an example. His social emotional development age is somewhere between 3 and 5 years. He can use a computer and loves watching children programs on YouTube. He has an above average autobiographical memory especially with respect to people who were with him. Most of the time, he knows who has been introduced to whom. He immediately notices when someone is missing who should be there. Very remarkable, because in general people are not good at this, especially not for groups over twenty people.

radicalbyte2• 7 years ago

Flowers for Algernon explores this issue and had a profound effect on me as a teenager. Probably the best book included in the school curriculum.

leemailll3• 7 years ago

Is his motor function affected?

fjfaase5• 7 years ago

Yes, his motor function is also affected, but has improved a lot, such that now as an adult, it is primarily his fine motor skills that are poor. But he has no problems using a mouse. The wear pattern of his shoes is still a little abnormal.

The poor motor function is probably related to poor myelination of the nerves in his body, as his proprioception and pain perception are affected.

xkcd-sucks• 7 years ago

Romantic relationships make lots of totally normal people very unhappy, to the point where perfectly healthy young people kill themselves over romantic rejection or kill partners for whatever reason. Learning how to do romantic relations is painful, and when it's not painful for a person, they usually experience the pain later when they get old or fall in with a terrible partner.

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.

samirm• 7 years ago

Happiness is only understood in contrast. On the one hand you obviously want to protect your child and ensure their happiness, but on the other, by doing so, you might be robbing them of the essential human experience. Happiness shouldn't be an end goal to a life, but a byproduct of one. Negative experiences shouldn't be looked down upon and avoided, after all that is how we learn and improve ourselves - by overcoming adversity.

Having said all that, this is an incredibly tough decision to make and is solely up to your family.

rohanseth4• 7 years ago

I'm really sorry to hear about your son. I'm Lydia's father (the author of the medium post). What you shared is my biggest concern about going forward with Lydia's treatment. We are confident that the treatment will help her brain development, but to your point, there's a chance that will hurt her quality of life. We just don't know. How do you make a decision like that?

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.

max2• 7 years ago

If I may make a suggestion (not sure if English is your second language or not). Consider using 'typical' instead of 'normal'. It took me awhile to get used to that but my daughter is better off this way.

ailideex3• 7 years ago

I’m Open Sourcing My Baby to Save Her and Others

Nope, that is not what you are doing.

rvz• 7 years ago

Exactly, I just read the title and it was very confusing for me to understand what the article was about.

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.

raxxorrax• 7 years ago

True, but this is one of the cases where I don't mind clickbait as much. Getting attention should be the goal.

OJFord• 7 years ago

Yes, that's really confusing, is it seriously only referring to posting photos on Instagram?

Even in that ridiculous analogy, that's sharing binaries with the source kept closed!

dusted4• 7 years ago

If a program was created in machine language, it's binary IS its code, you don't need the abstraction. If you chose to share this data freely, it's open source. Even if you just play on the words; You open a source of information.

bayesian_horse3• 7 years ago

He may be talking about publishing genomic sequence data, and the data on the treatment he/they created. Maybe some tools to come up with such a treatment.

ailideex3• 7 years ago

He should be more specific. Conflating a treatment for some illness with a human infant seems needlessly careless use of language.

Keyframe• 7 years ago

Would that even be legally possible?

amdavidson• 7 years ago

In a way, that is what he is actually doing:

  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.

ailideex3• 7 years ago

I'm not sure how you get from open sourcing "process, costs, contracts, protocols, assays, cell lines and data" to open sourcing a baby as "process, costs, contracts, protocols, assays, cell lines and data" is not a "baby" nor is it the source code of a baby.

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.

mkl• 7 years ago

On the face of it that's just publishing. Open source is more about the license you publish with.

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.

sbarre• 7 years ago

This feels like possibly the worst article for you to be coldly pedantic about?

I know it's an HN tradition, but empathy is important, friend.

rohanseth4• 7 years ago

Yup, that's fair. We took some creative license here, but couldn't quite figure out how to succinctly explain that we want to go beyond just academic publication and share everything.

mangatmodi3• 7 years ago

So there is a cure, but it is not profitable and no body is doing it? Society has evolved so wrong, when we can't provide basic needs to everyone despite (probably) having enough for everyone.

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?

carlmr4• 7 years ago

Society has evolved so wrong, when we can't provide basic needs to everyone despite (probably) having enough for everyone.

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.

mangatmodi3• 7 years ago

@carlmr, I understood the position better now. Maybe states should completely fund or control medical researches. This is one thing which should never be done for profit.

luma2• 7 years ago

While I agree with your first point, I think you're off base on the second. If, as the OP suggests, it would be possible to develop a toolkit such that the concerns about time/resources you raise in your first point are moot, then I think it's worth chasing that down. The result isn't saving 3 people but rather making it possible (profitable?) to do the same for anyone with these sorts genetic transcription errors.

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.

not_a_cop75• 7 years ago

it seems like business people need to wrap their mind around creating a process that allows these one off solutions to be made more easily. There are probably over a million people with a one off genetic problem that would be worth at least 100,000 to solve. Making a one off solution once is obviously not the solution, but instead engineering the process to allow the one off solutions to be generated more quickly and easily.

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.

gridlockd2• 7 years ago

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.

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.

kartan• 7 years ago

Do I have to Ph.D in every medical science to make sure my kids get a treatment what they deserve?

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.

benj111• 7 years ago

I think might be misunderstanding this. Its more akin to developing an entire new medicine than applying a diff patch.

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.

thrav• 7 years ago

I had 2 experiences recently where an acquaintance would’ve died, if not for called in favors to doctors who were personal friends.

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.

grandinj• 7 years ago

That's actually just a thing called "fallibility".

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

logiclogic2• 7 years ago

Let's just agree it is broken and do nothing about it. We have connections after all and only the other people will suffer so who really cares.

navigatesol• 7 years ago

Do I have to Ph.D in every medical science to make sure my kids get a treatment what they deserve?

Not necessarily. What are you doing to contribute?

mangatmodi3• 7 years ago

The best I could do, a responsible citizen. Taking care of others as much as I can.

quickthrower2• 7 years ago

It might be worth reading through https://80000hours.org/key-ideas/. There is a lot of much lower hanging fruit if you want to spend money without the profit motive, to help people.

fevangelou• 7 years ago

If modern medicine was 10% open source, the world would be 110% a better place.

blueboo• 7 years ago

Something weird is going on with this lady...wasn't the campaign originally 1 or 1.5m? Now it's 2.5m for a vastly more ambitious goal?

Kickstarter tawdriness is creeping into what was otherwise a gold-plated medical GoFundMe.

rohanseth4• 7 years ago

This is our bad. When we had shared at Google, we thought the cost would be $2 million. We didn't include the money we had put in or received, so we shared our goal as $1.5million.

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.

fareesh• 7 years ago

What does it mean to "silence" a mutation? If that particular gene is different compared to humans who don't have the same developmental condition, then is the medicine able to instruct the cells to replicate in a way that ignores the mutation and not carry the defect created by the mutation?

Or does the medicine supplement the role of whatever that cell is supposed to do? (Assuming this affects some specific roles cells)

sjg007• 7 years ago

There are two alleles for this gene. You get one from your mom and one from your dad. In this case one allele has a mutation that is causative. So you inject some anti-sense RNA matched to that mutation, it will bind to the mRNA of the transcribed mutated gene DNA. Since it is now bound up, the mRNA cannot be translated by the ribosome and turned into protein. This means that only the other allele (without the mutation) is translated into protein.

ausbah• 7 years ago

This sounds like an absolute lifesaver for a bunch of people! I'm surprised more people in the comments aren't even a little more enthusiastic.

remeq• 7 years ago

Playing around with words like "open sourcing" is not a good idea in semantics-sensitive dev community. Not even what it comes to pretty little babies

dusted4• 7 years ago

It is an excellent point, genetic mutations may have wildly different consequences, but they are all the same fundamental issue: genetic mutation.

dusted4• 7 years ago

The article makes the excellent point that, although various genetic mutations have wildly different consequences, the root problem is the same: Genetic mutation. Sounds like there should be a generic fix somewhere.

twodave• 7 years ago

I mean, you'd have to have a reference genome basically, right? How do you even define such a thing...

shultays• 7 years ago

I am not a doctor but i would imagine most genetic problems would be too late to fix once you are born. And the one that are fixable would require you to fix syptoms rather than dna itself. So "a generic fix" is probably impoasible

mikepurvis2• 7 years ago

It might be too late for today's babies, but if you could build a big enough catalog of mutations and suspected/confirmed ill effects, then you'd potentially be able to catch thousands of these mutations essentially at conception and supply a custom therapy right then and there to correct it before any brain development has begun at all.

dusted4• 7 years ago

It may be, there may be several classes of "generic fixes".

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)

inmate4587• 7 years ago

Well.. it is an excellent idea.

elcomet• 7 years ago

"My haby"

alberto_ol• 7 years ago

the typo in the headline should be fixed

b_tterc_p• 7 years ago

The headline has changed for me to include a typo? “... sourcing my haby”?

ModernMech• 7 years ago

Only reason I clicked was to find out what a haby was.

monkeydust• 7 years ago

Likewise. Guess it worked then!

dlphn___xyz• 7 years ago

its crazy how people support medical experiments on a child but will call child protective services if you feed your child a vegetarian diet

amthewiz• 7 years ago

Who does that?

Xelbair• 7 years ago

One can lead to normal life for the child if the condition is severe. Not doing anything can hinder child's future, while medical experiment can save the child.

Other has no positive benefits, while it can be dangerous to the child.

logiclogic2• 7 years ago

I know many parents who feed their children a vegetarian diet without any health issues whatsoever. The cases I have read about in the newspapers were parents feeding their kids a vegan diet without a sufficient amount of calories and their kids literally starved from not getting enough energy to live. You can not live off eating only tomatoes and salad every day but you will be buff if you eat beans and lentils every day. Edit: A vegan diet requires more knowledge to get all the sufficient vitamins and these parents obviously fucked it badly.

acomjean• 7 years ago

There is a whole network of undiagnosed diseases. They’re getting better at replicating these mutations in model organisms which can help figure things out faster and less expensively.

https://undiagnosed.hms.harvard.edu/

DoreenMichele4• 7 years ago

For Lydia’s, there are only two others in the entire world — one in Greece and one in England.

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...

deskamess• 7 years ago

Parental hurt is an altogether different kind of hurt. I have felt it in a few cases but 'life struggle' issues are likely on another level. I can empathize only to the limits of what I know and can only wonder how, and hope, they continue to stay strong.

kohanz• 7 years ago

This. My heart aches on a whole new level when I hear/read/experience children and parents going through such hard things. We've had very close friends lose children at a very young age and it's heartbreaking.

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.

ycombonator• 7 years ago

This is heartbreaking. Thank you for bringing the awareness. Hold that child tight.

JPLeRouzic• 7 years ago

Would not it be possible to create an open source project for a generic platform for antisense oligonucleotide therapies.

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?

rohittidke• 7 years ago

I am trying to donate from Germany but can't because of an error. Not a valid phone number. Any body faced the problem?

lettergram• 7 years ago

I’ve seen the title of this article change at least three times. I actually think the “saving Lydia: open sourcing by baby” may be the most descriptive.

vasilia• 7 years ago

Hope that will help Lydia to have a good long life and other people.

Causality1• 7 years ago

Excellent article. It's my belief the medical industry suffers from a "take no action" bias. They believe letting ten thousand people die from inaction is better than a treatment that will kill half of them and save the other half. When it comes to people who are going to die or suffer for the rest of their lives, I don't see anything wrong with "move fast and break things".

AtlasBarfed• 7 years ago

Genetics-specific treatment is what medicine should be working toward.

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.

dmix• 7 years ago

I don't see why you repeatedly accuse MBA people or the pharma scientists of not "caring" then proceed to explain multiple reasons why it's infeasible as a private business or even an academic or public organization.

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.

hkai• 7 years ago

With whole exome sequencing now at 500 USD, personally I will start by testing myself and my partner for hereditary diseases before having kids.

Saving Lydia

Related Stories