#16 - Noor Siddiqui - Is Embryo Screening the Future of Reproduction?

24:51They'll say, okay, we're only going to look at recessively inherited disorders. You know, there's dominant disorders, there's so many different things, but we're only going to look at this really small fraction and that's the extent of what carrier screening is. And I think that that's, you know, it's paternalistic to say those are the only conditions you should worry about. There's plenty of people who, you know, they want to mitigate the risk for hereditary cancer, right? They might have, you know, BRCA, right? That's not included on most carrier screens. So I think it should really be up to the parents how much information they want, what risks they want to mitigate.

25:23And I really hate when people minimize other people, right? So some people will say, well, why would you be worried about schizophrenia or bipolar or Alzheimer's? It's like, if you have a family member with that condition, you know and understand it at such a deeper level what it actually means to live with that condition. And I just hate seeing people minimize and say, oh, well, you shouldn't worry about that because of the base rate or because da-da-da-da. It's like, well, if you have firsthand experience with it, you probably know a lot better what it means. That's the thing. The families that are actually at risk of it are the ones who probably already have more information.

25:57And so it's, yeah, I do agree. it seems a little poor taste for people who have no insider info of what it's actually like to experience that and pass that on. Yeah, and they're not on a hook for the lifetime of medical bills, the huge emotional burden, the huge physical burden. I mean, these families are heroic, right? They completely reorient their lives. They start nonprofits. They do incredible... One of our first early users, he literally self-compounded a drug at home that was totally out of commission in the entire world because his daughter had a mutation in a gene called KCNQ2. There was only like three other people in the world that had it.

26:34He contacted the one family who was a survivor. One in a billion type thing. Yeah, and it sucks, right? You have a spontaneous mutation that affects your kid. I mean, okay, it's rare for someone else, but it's your life, right? And the fact that anyone would try to attack someone like him or someone in that category for maximizing the amount of information so that their next child doesn't have to be affected, I feel very strongly about that ability being on the table for the people who choose it. Yeah, I think one thing that also is often the underlying cause for people disagreeing with some of this is kind of related to status quo bias or like the naturalistic fallacy where there is an inherent assumption that, yeah, you have babies the normal way if you can.

27:19and there you just roll a die and whatever comes out comes out and that's the baby you were meant to have. Yeah. And it's kind of odd where, oh, and then you had a miscarriage and you were meant to have a miscarriage. I don't understand whether that's then the case and you were meant to have the next baby and then it comes with a certain set of genetic diseases and you were meant to have them. It seems very weird that there would be such a strong kind of, like stance behind it? I think that reproductive technology specifically is super plagued by this, right? So if you look at the history of reproductive technologies, so something like epidural, right?

28:01Like pain relief during pregnancy was incredibly stigmatized. You think it seems like obvious, right? Why, if, you know, if a woman's in pain, why would you not help her, right? But then there was the church and this desire that, you know, well, you know, women are supposed to be, you know, birth is supposed to be painful, right? Right. Even to this day, it's stigmatized. It's seen as, oh, you know, somehow natural childbirth. What does natural even mean? Somehow that, you know, without a medicated childbirth is somehow inferior, right? There's like this weird machoism among women for delivery where, oh, I didn't need to, whatever.

28:32So I think that, again, it's really just about offering the choice and not stigmatizing the choice. For some people, they have, you know, there's a huge variety in birthing outcomes, right? People literally die during delivery. People have hemorrhage and have insane complications. And then there's also, on the other side of it, people who have orgasmic births. Why would you demand the woman who's having an orgasmic birth to do an epidural? No, she's enjoying the experience. Let her be. But for someone who's... I am sorry, there are orgasmic births? Yes, it's very rare. But yes, some women orgasm during birth, during delivery.

29:07Huh? Yeah, it's a thing. I wish we could have more of it. That needs to be studied. I agree. You want to fix birth and fertility rates. Because I mean, frankly, that's one of my biggest, I mean, I don't think it would be my, that's not the thing that's been holding us up or giving us difficulty, to be clear. I know, that sounds like really exciting, right? Wow. Yeah, so it's bizarre how much of a range there is. There's a huge range. So the point is, there's no one size fits all. Yes, there's no one size fits all for anything. So anyways, I guess kind of going on my rant about reproductive technology.

29:37So epidural is just, it just pisses me off that people stigmatize that. and it's still stigmatized today. With the stigma, I wonder, like the thing that with all of these naturalistic arguments always struck me is, like, where is the cutoff from nature to non-nature? I don't quite get. Like, it is, like, God gave us, in that view, God also gave us free will or free choice making, right? And an amazing brain. That was the main thing, exactly. And now we're not allowed to use the brain to create medicines. And if it's grown as a plant and it functions as an epidural, that's okay. But once you put it into a syringe, like where's the cutoff?

30:19No, but here's the other thing that really pisses me off about that specifically. It was okay for men on the battlefield. It was okay for when your arm is broken. But then when you want to use it for women during childbirth, that's when it starts to become... And that's what I think is interesting about reproductive technologies. There's a specific sensitivity around childbirth, around how women should have babies. So the other kind of example is birth control. So when birth control was first introduced, it was literally criminalized in the United States. It was against the law. There was obscenity laws.

30:52It was considered obscene to use birth control. That's something that we totally take for granted today. Does that include condoms, or is it just the pill itself? The pill itself. The pill was marketed initially under something else, right? And it had this side effect as well? That was basically the second stage of it, right? So after it was stopped being criminalized, then it was, okay, now your husband has to approve it. So you can't use it if you're not married. So now your husband has to sign off on it. And then it was, you have to see it. It's always this intense process to give women choice and give people choice, right?

31:25And then similarly, IVF. IVF was considered just this horrible affront to humanity. And it's just every single technological advance in reproductive technology, you know, from epidural to birth control to IVF, was always this, like, heated, intense debate. And I think the same thing is happening with embryo screening. I think that, you know, we're going to look back on it as, like, the same as the way we see birth control. It's like, oh, my God, obviously I'd want to choose when I have a baby. And, you know, obviously I'd want to have, you know, paid relief, right? Like, there was also this huge, you know, strife, and there still is to this day, about, like, home birth versus hospital birth, right?

32:04So hospital births, you know, you have really much lower rates of, you know, infant and maternal mortality, right? But, you know, there's lots of women who have lower-risk pregnancies. Let them give birth at home if they want, but they're criticized, right? And then women who are in the, you know, who choose to give birth at the hospital, they're also criticized. So it's just like, I think we just need to have a little bit more empathy that your life decisions are yours. Yes, exactly. Right. What do we know about trade-offs? I take out the genetic disease and damn it, I also killed their ambition.

32:37Not ambition, but something more likely, like now they will never have brunette hair. I think this is like an incredibly interesting topic. So I think one of the examples that's probably most well-known is if you have sickle cell, you actually have resistance to malaria. So that's an interesting genetic trade-off, right? So that's why you see a lot more of sickle cell of that condition in Africa, because there's much higher rates of malaria there. Nature selects for it, essentially. Yeah, exactly. So there are these interesting situations where there are genetic trade-offs. That's basically a monogenic or single gene example.

33:13Is it because it is the same gene that does both, or is it that they are next to each other? It's the same gene that does both, right? So basically, the thing that gives you sickle cell, the way that it changes your blood cells, is the same thing that makes you very resistant to malaria. It just has to do with how it affects blood cells. The way that you see it much more often is actually, I would say, with polygenic conditions. So with polygenic conditions, you're talking about the cumulative effect of millions of genes. So typically, the correlations are associated with a similar category of conditions.

33:51So if you're more likely to develop schizophrenia, it's also associated with bipolar disorder and a lot of other psychiatric conditions. Similarly, for heart conditions, if you have high risk for heart disease, it's also typically higher risk for asial fibrillation, other sort of cardiovascular conditions. So there's also a lot of labs that are doing these giant maps, these correlation maps of like, okay, but what about positive and negative correlations for all of these? So I'd say some of the trade-offs that have been found is sort of there is a trade-off between schizophrenia and creativity.

34:24So, yeah, I think this is like a really super interesting area. And I think the trade-off, the impact of trade-offs, I think, is a little bit overemphasized because of this like canonical example, I think, of like sickle cell and malaria. And I think that people don't give enough credit to the sort of, I would guess, like free lunch argument of like, okay, well, a lot of psychiatric conditions are actually correlated with each other and a lot of cardiovascular conditions are actually correlated with each other. So what's the stage of the science on the polygenetic markers then currently? Because I would imagine it sounds like it's more complex.

34:59You're looking at many more genes. Is it in many cases we kind of don't know very specifically whether it increases or reduces the rate? We're very good at stratifying risk. So what that means is that if you're in the 99th percentile of risk, so let's just back a little bit on how they work. So the way they work is that you take really large cohorts of people, and then you say, what are the variants that are correlated with the disease? What variants are enriched in people with heart disease that people without heart disease don't have? You have these labels, lots of SNPs, and then you have this label of did they get a heart attack or not.

35:37So you build this model, and then what you end up with usually is that people on the 97th, 98th, 99th percentile, they have the disease at 3, 4, 5, up to 10 times the rate compared to average. So average being the 50th percentile. So people look at that very differently, right? So some people will say, oh, I definitely don't want my embryo to be five times as likely to develop heart disease. Other people will say, oh, well, you know, well, the base rate of the disease is low. oh, so even though, okay, so for example, you know, for something like schizophrenia, I think the base rate of the disease is 1%.

36:10So even if you're, you know, five times more likely, okay, that's 5 % versus 1%. So they'll say, oh, 4 % is a small difference, right? But well, if you compare it to the alternative, which is, well, there's no diet, exercise, medication that reduces your risk by 4X, then it sort of seems more powerful. So it really just depends on how you frame it. And again, I don't think you should make any opinions about what is the absolute risk reduction or relative risk reduction or percentile reduction that is meaningful. What's meaningful depends on what's important to the family and what the alternatives are, right?

36:41So for something like heart disease or diabetes, okay, maybe your lifestyle can manage and mediate that disease a lot more. Much more is known about how to manage it, right? For something like, you know, maybe schizophrenia or bipolar, well, there's not as many alternatives for people to consider. I think another example that I think people are more familiar with to understand the difference between maybe polygenic risk and monogenic risk is smoking, right? So smoking, you know, massively increases your risk for lung cancer. But if you actually get into the nitty gritty of how much it increases your risk, you know, I think it sometimes can surprise people.

37:13So let me just pull it up because I don't want to get the numbers wrong. So basically, if you smoke one to five cigarettes per day, you have an 8 % lifetime risk of developing lung cancer. And lung cancer is typically diagnosed at about age 70. And if you have 35 plus cigarettes per day, then you'll have a 26 % chance of developing lung cancer by age 80. So in other words, you have a 90 plus percent chance of not developing lung cancer if you have one to five cigarettes per day, and you have a 75 plus percent chance of not developing lung cancer if you have 35 plus cigarettes per day. Some people would argue, oh, that's a 9 % difference.

37:47So 90 % of the time I'm not going to develop the disease. But that's massive. I think people just literally just don't understand how to interpret the numbers. I'm not saying that you should smoke. Smoking is bad. It is insane. You do not want to be 10 times more likely to develop a disease. 10 % is a, you should not put up with that. So anyways, I just think people sometimes will minimize these single digit numbers because they don't understand the framing of there is no alternative. And yeah, basically like there's plenty of like blockbuster drugs that are making drug companies billions of dollars that are moving, they'll say 45 or 50 % relative risk reduction.

38:24But then the absolute risk reduction is like water 2 % rate of heart attack reduction. So anyways, this is like a, it can go on an arbitrarily deep topic, but I think with giving people information, you also have to put that information in context. And that context should not be deceptive, right? So I think it would be correct to argue that displaying relative risk inflates it, right? Because you're saying, oh, 60%, 70 % because it sounds bigger. But it's also deceptive to only do absolute risk and to not present the alternatives. It's not talk about smoking, because it all helps framing, well, how much does any specific thing that I'm investing in actually move the needle in my child's health?

39:01Let's say this technology becomes ubiquitous and cheap, so that everyone, now this is the way that you have babies. No one is having, or very few people are, basically, yeah, very few people are having natural conception. Sex is for fun, IVF is for babies. Sure, sure, sure. We barely understand, I'd say we don't understand, how genetic diversity really works and the complexity that is arising from it. Because it seems like throughout nature, when things have evolved, even these horrible diseases, it's rare that there are accidents, right? Or at least there seems to be some evolutionary purpose to these things.

39:44So is there a risk that by eradicating a realm of diseases is from the gene pool that we are messing with something we just don't understand. Yeah, it's like a super interesting thought experiment to go down. So I think that, so I guess first layer of it is that, so kind of this whole, this objection is sort of like unknown unknowns. We don't know what it can't do. So yes, there's always unknown unknowns, right? So even when you have a drug go through a clinical trial, well, what if in 40 years the person drops dead because of the drug, right? It's like we never let the criticism of unknown unknowns stop us from almost any other technological or medical innovation, right?

40:22We test all the things that we can test, and then the unknown, there's always an expanding set of them. So that's just my general criticism of the unknown, unknown argument. But then specifically, the idea of reducing genetic diversity, I think that that's interesting, but I think that specifically for this current way that embryo selection would be done, it's not a huge risk. because the embryos that you create are the natural variation between the two partners. So you're not really reducing the variation of genetic diversity. I mean, I guess if people only have one kid, then you are because they're not having three or four or five, the number that they were usually having.

41:02So you do have a reduction in genetic diversity just by the number of kids that people choose to have. But in terms of the natural diversity that exists, you're just sampling from that. So there's that. Second, there's a huge class of the conditions that we screen for that you look at that results in basically people who are not able to have kids, right? So these are, you know, birth defects that result in, you know, childhood death or early adulthood death are basically a consequence of some of these conditions is infertility. So, you know, some of these conditions are so severe that people are not able to live alone or to, you know, have kids of their own.

41:38So for that other set, it's not really changing the overall genetic diversity. but I think that if you get into the situation where there's lots of these polygenic conditions and for some reason there's some meme in society where everyone gets obsessed with one specific combination you could end up shifting one way or the other but I think that's a pretty extreme and remote possibility because even with the power of mimetic desire today on the internet there's always that person who wants to be more contrarian. It's like, oh well you like red, I like blue, or whatever type of thing. So I think that at least something that I've been surprised by is that I think people's preferences for their kids are actually more diverse than people think, right?

42:22So I think the canonical example people always give is like, you know, if you could do traits, to be clear, we don't do traits. Everyone would select like blonde hair, blue eyes, right? But I wouldn't do that. They wouldn't look like me. So I think a lot of times these criticisms people have reflect a little bit more, you know, their own prejudices about what they would want personally, which again, I think is fine. They should be able to select what they want, but it's not necessarily representative of every single person's preferences. For example, even with the limited that we can test for right now, some parents have chosen they want to have a child that's deaf and other people have not.

42:55So this is like, even in a very limited amount that we have been able to do historically, we're already seeing that diversity. Obviously a big fear when I was reading about this and so on is like, okay, when have the issue, the topic of designer children, and eugenics basically been issues in history. It's been when there's been centralized, top-down control of crazy people trying to control what the population looks like. And while I think it is true that this technology, genetic screening technology, in theory, could enable such a thing to happen more, at the same time, the technology is hand-in-hand with allowing individuals more choice.

43:43And from what I understand, concerns of eugenics is when it's basically taking people's choice away. It's basically saying, no, these types of people are wrong, these types of people are right, and it's coming from a very centralized point. Yeah, yeah, I totally agree. So basically I feel like the strongest possible, I'm really against the idea of any sort of government control, physical physician control or any sort of not the parents' control of this information? Because yes, I think it does lead to these horrible abuses, right? There shouldn't be any centralized authority saying, you know, this is good or this is bad.

44:19That's where I think the problems lie. And that's, you know, where we see this horrible, you know, history in the United States of forced sterilization. I mean, this is like the most, the worst, you know, affront to humanity to say to some person because of whatever property, you know, you don't get to have a child. That's the exact opposite history of IVF, right? IVF is saying, even if you're infertile, we want to give you the ability to have a kid. And now it's expanding that scope to no matter what disease you have in your family, you have more choice and more opportunity to mitigate that risk of the next child based on your own personal preferences.

44:52So that's, I think, one reason why I get really activated when they're kind of lumped together because they're literally the exact opposite thing. One thing is saying some people shouldn't be able to have kids, and the other thing is saying, no, we want the maximum number of people who want to have babies to have a healthy baby, whatever healthy means specifically to them. I mean, sometimes, though, the choices I think have also been made by parents where you look at population pyramids of certain countries, you see that through some age bracket they have many fewer girls than boys. And it looks horrific when you actually look at it because of the implication of what must have happened at the time.

45:31But actually, I think they've gotten there, sadly, without IVF. They've gotten there by other terrible means of actions. Yeah, I think it's also a really difficult position that we're putting pregnant women in now, which is like, okay, you find out about trisomy 21 Down syndrome or whatever when you're already 10 weeks pregnant. And I personally, I think everyone should have the right to a termination if they want one. But it also is really difficult to make that decision, right? It's extremely taxing on the body. It's extremely taxing emotionally. So I think that's another thing people don't realize is that when you screen embryos, you're able to identify risks for all of these at once so that you actually lead to fewer terminations, whether that's, you know, natural termination, meaning a miscarriage, or it's an elective termination due to the very, very, very small number of genetic diseases that you can detect once a pregnancy is already in progress.

46:23Right. We have some of the screening is already part of most IVF procedures and done and legal in the U.S., right? Like Down syndrome, for example. Yeah, exactly. A number of others, like in my case, Tay-Sachs, which we did. Yeah. Yeah. So So basically, you're adding a few more for the large number more, I suppose. Yeah, thousands more. But I guess the distinction I'm specifically making is like, it sucks to make the decision once you're already pregnant. And like, for me personally, I would rather avoid everything possible before I'm pregnant, even though I am. Like, that's another thing I think people don't realize is that, you know, you can be, you know, pro-choice, pro-termination, but also acknowledge that, you know, a termination is taxing.

47:05And you, a lot of people want to minimize it. And I think people just don't realize that there's this door on the left, which is okay, but if you screen your embryos, then you're more likely not. We're avoiding this problem in the first place. So in theory, that should placate some of the pro-life lifers as well, right? Yeah. I mean, I don't know. Or it makes them more upset. Depends on what they define. I mean, if they define the moment of conception, at the same time, I think there's a scale of people as well. They're not a monolith. Yeah. Right. Same as the pro-choice people are not a monolith.

47:37I have an intuition that the earlier in the embryonic to baby process, you make that decision, the better. Yeah. Right? Provided to a nervous system being developed and so on, which presumably at the blastocyst phase, it's just... You can't even see it with a naked eye. Or don't have sex in the first place. Well, that's the way the society seems to be going. So actually, on that note, I would love to pick your brains a bit on the fertility crisis. Yeah. Because looking at the numbers in, I mean, it's not even just the Western world, even like Bangladesh was a shocking one, right? That was, I think it was at five babies per woman 30 years ago, and now the number's down to two.

48:19Yeah. So around replacement levels. So it just seems to be a trend across the world that fertility rates are dropping. Do you have any particular suspicion of something that's driving it beyond just preferences? Because if you don't mind me saying, we have not been on birth control for years, and we've never gotten pregnant. And that's always made me wonder, what's going on there? We're pretty healthy people. And we've also not been celibate. And we've also not been celibate, yes. There would be another explanation. There would be, yeah. But not that either. And just speaking around, yes, okay, I'm in my late 30s, but I was in my early 20s when we got together.

48:57And speaking around to other people, it just seems the rate of fertility issues in otherwise healthy couples is going up. So is it just the microplastics? What is it? Yeah, I mean, unfortunately, we don't know. But yeah, we think that there's just basically this growing body of evidence that phthalates and basically all these different microplastics, they're endocrine disrupting, right? So your endocrine system is what derives your testosterone levels, your estrogen levels. And yeah, male fertility is plummeting, right? So now I think the sperm counts are sort of 50 % what they were about 30 or 40 years ago.

49:32And we don't know why. We think it has to do with this constant exposure to chemicals. But it's also so difficult to study and disentangle because it's just like nutrition where it's like, oh my god, there's thousands of different exposures. You ban one type of plastic or BPA or whatever, and then they just replace it with another that's slightly modified. There's this cat and mouse game, almost like security, with all the different chemical exposures. right? So, I mean, yeah, but what we do know is that in industrialized countries, yeah, men have much, much lower sperm counts. But what's nice is that they, since they have so much sperm, it's, you know, usually still okay.

50:08You can get rid of a few million. Yeah, you could. No. So I think it's, I think a normal, like, I think a milliliter of sperm, like, you know, should have like almost like 100 million. And now it's about 50 million. And then basically sub-fertility numbers are sort of like 30 million or something. That's what kind of, Most men, I mean not most, but a lot more men than previously are on the edge of being subfertile. And I think for IVF they use like 20 ,000 to 50 ,000 sperm or so that get into their chemical style obstacle course, it was explained to me, until the one winner comes up. That's another thing.

50:38Sperm Olympics. Yeah, there's a sperm Olympics. And the other thing that's so crazy about sperm is that people don't realize how many sperm are abnormal, right? So like three tails, no head, like all this insane variety. Like I think, I'm forgetting the number, but I think it's something like normal morphology is something absurd. Like 95 % abnormal and 5 % normal is like good. And I was like, what? So yeah, I don't know. Sperm is really insane. The other thing I thought is really insane is that semen is actually like kill, like can kill eggs. So semen is like only needed as a vehicle to get the sperm to the egg.

51:15But the actual exposure of semen to eggs will like kill them. So they learned this when they were developing IVF, because you have to do these really aggressive washing steps, right, to like mimic what happens in the cervix. And yeah, it's basically just like, it's like almost like this poisonous road that they're taking to the egg. Wonder why that would have evolved. Maybe to kill more. So that the best, I don't know, who knows? But yeah, basically, yeah, during IVF, they do the same process that, mimic the process that happens naturally, which is like you have to do this intense cleaning to make sure that that sperm that hits the egg is not contaminated with semen.

51:47Which is apparently toxic. Who knew it was toxic? But yeah, fertility crisis, just to, like, I guess riff on that point is, like, I don't think people grok that, okay, I think when you say these numbers, like, oh, 1.6 or 1 or whatever, all these numbers of how much fertility is falling, it's like, okay, what that actually means mechanically is that the population cuts in half by 50%. Like, you have 50 % fewer people. Okay, that's a huge deal. It's a really big problem because it means that all of our, you know, all of our social support systems collapse, right? You don't have people contributing to society to make it so that Social Security and all these retirement benefits actually exist.

52:21They suddenly collapse under the demographic pressure. You don't have as much innovation because there's not enough young people who are making new things. It's a huge problem. In getting to the symptoms or why we think it's happening, I think some of them are pretty obvious. careers are basically education and the amount of time it takes to establish a career is taking way too long. Women in medicine have twice the rates of infertility as outside because it's like, okay, they're in school for seven years. 15 or something. It's horrific. I think that's a super obvious one that we could probably fix.

52:57But I think the more insidious one, which I don't know if you feel, but I just feel like on the coasts, I think that being a mom is just stigmatized. It's not celebrated in the way that it used to be. It used to be that if you're a woman and you're a mom, that's like, oh my God, you're amazing. That's so cool. And I really think that that's shifted. I think now it's stigmatized. It's like, oh, you're just a stay-at-home mom. Or why don't you also have a career? And I think, again, it's kind of going back to that choice of true freedom means that none of these paths are stigmatized. It's like if you want to be focused on your kids for however many years, that should be celebrated.

53:31If you want to be focused on being a CEO or whatever, maybe quote-unquote previously conceived as a masculine notion, then go celebrate that. But I think right now women are caught in this impossible thing of like, okay, you have to do 100 hours a week in your job and then 100 hours a week in your kids, and then basically they're caught in this impossible thing. They'll just die the rest of the time, yeah. Yeah, yeah, yeah, exactly. I don't know how you feel about it or what you think is going on with your friend group or just, yeah. I mean, at this point, most of my female friends, certainly the ones of my age, have had kids.

54:06For me personally, I just never had much of a desire. I was never one of those. My cousins, who are also girls, were very interested in dolls as children, and I hated them. I just wanted my planes and my cars. And I've never had the same level of maternal drive as other women. I'm only starting to feel it now in my late 30s, which is one of the reasons we pushed for like, okay, let's get ourselves some optionality because I'm getting old and we've got to, these eggs are shriveling up. So I'm very glad we did that. But it's, yeah, and I think in part that came from, now whether that was from society or something that was just within me from a young age, but I, yeah, the idea, I never saw myself as being satisfied from being a mother, at least solely.

55:01I've always been very career-driven and wanting adventure, and I associated having children with, like, giving, like, that's no more adventures for you. Which, obviously, it comes with huge trade-offs. Like, you can't now just up and go to the Himalayas or whatever. Yeah, so I think this is a great point. So, basically, I think I fully sympathize with that. And I think I've been, like, really inspired by listening to, like, I don't know if you know Julia Hartz. She's like the CEO of Eventbrite. But she talks about how like there's, and then I think Robin Hanson talks about this too, about basically there's way too much parenting effort, right?

55:34People think that like when you have kids that like, okay, now you're a bad parent if you just go and take them to the Himalayas randomly. Or like you're a bad parent if you don't like completely reconfigure your life around them. And in the past, it wasn't like that. In the past, it was like the kids did their thing. I mean, again, I don't have, I'm not that old that I can really speak from experience about how parenting was 60 years ago. But the pressure on parents to reorient their lives, I think, is too much, especially since it's in combination with less integration of family. It also used to be the case that grandparents— Grandparents, huge.

56:06So it's like you're cutting off childcare that was built in, and you're cutting off independence at the same time. And I think that these conceptions are really tough to break. But I think at the same time, I think what you're saying, you know, you shouldn't lie to yourself, too, about, like, how your life is going to change when you have kids. So it's like a combination of, like, having good mental models of, like, breaking the stereotype and doing what feels right for you. But also acknowledging that, okay, yes, like, this is a, like, living, amazing, you know, human that needs to get nurtured.

56:38And, like, what does that, you know, what does that involve? I think a good way to look at the fertility crisis that I think is the most useful framework is to consider it from the lens of opportunity costs and taking an economic lens. So we've seen fertility rates go down in all of the developing countries when they become richer, right? And female education opens up. And what happens is that your opportunity cost from having children grows because your opportunities increase in number and quality consistently. So it becomes very rational, actually, to have a higher threshold or higher need for children at that point.

57:21And that's why you see them go down. And if you take that perspective, what would help to increase fertility rates? again what many countries have tried is something like child support by like basically paying them right but that only goes so far i think only czechia succeeded and other countries have tried it goes back down usually but the what what has also worked is what you could imagine is like if you did the evil version of it and you flip it it's like take away female education make the country poorer and then probably fertility rates will go up again as well but that's the bad version Don't put out ideas.

57:56No, but I think it helps to think about it in that way. Don't you feel kind of weird? Is it like historically somehow that women had no other choice, basically? Is that what I want to say? Well, I think historically it was a value you could provide to the family and the tribe to make more children that then can keep contributing. And you didn't have that many other things to do probably as well. Now you have many more options. So I looked at it as I was working on giving grants to various increased fertility rate efforts. And you can basically reduce the costs for having children or increase the benefits from having children.

58:36We actually touched on this just now on a number of these, right? Increase the benefits would mean, for example, doing stuff like what you touched on culturally. It's culturally just not as respected anymore as it used to be. And that is a benefit that you could increase. Reducing costs could mean either child support, or it could also be in the benefit side, or increase help with child care would also improve it. Or like the SNU is great, right? It reduces the cost of when you actually have the child, what you have to do. But actually, that is why I got interested in IVF and genetic screening in the first place.

59:21Because, as I understand, like you were 36 when we did it. And natural conception at 42 would have become unlikely and very difficult at 45 now. Basically, a very, very rare thing. Whereas if we do IVF at 36 and then implant it into you at 42, the success rate is many, many times higher than 36, right? So the cost to the woman from having children goes down if you can do your life a bit longer and have the child at 42 rather than at 36. So I think that's a great opportunity. That opens up from it. And that's why I was looking into investing into various fertility companies because I think the world will need it.

1:00:06As you pointed out, the dependent to contributor ratio is currently going to the dumps, like really, really heavily. What do you mean? Well, in each country where the fertility rates are dropping, you have an amount of people that are currently contributing to the social welfare system and other people that are depending on the social welfare system. And actually, if you look at it on the population pyramids, the widest section in most Western countries is like the late baby boomer stage and a little bit beyond. They're currently in their 60s, early 60s. They'll be probably not contributors anymore.

1:00:44It's kind of a mean word to use, not a contributor anymore. Like, they were contributors. But still, that's the term. In like five to ten years. So then we'll have a little bit of a step change where now you'll have, instead of like that rate, it's going to drop quite significantly and absent AI and robotics, we will need something to come up from somewhere to have social welfare systems still work. And it's either go poor, no social welfare, or have more children or immigrants, right? I think we should have probably more children and more immigration, both. But yeah, anyway, I'm really into IVF because it allows for more children.

1:01:23Yeah, I just think that it's super interesting that, yeah, basically a younger egg in whatever age uterus ends up with, yeah, basically super high rates of healthy kids. It's just like, it's so cool that we figured that out. And it's so cool that it's, you know, it's a consequence that is able to help, you know, not just people with infertility, but basically anyone who just wants to extend their timeline, right? But the other thing that I think is really interesting about IVF and, you know, embryo prioritization is that basically it used to be that IVF was just for people with infertility, but now so many people are electively doing egg freezing.

1:01:57They don't have any infertility issue. They're doing it because of this optionality of, okay, well, you know, they want to have kids after 35 or after 40, and how can they do that in a healthy way? And another thing that I think is really underappreciated or not understood is that, you know, you might be able to have that first kid by 35 or 40 or whatever age, but then now what about if you want to have two or three kids, right? So that's another thing that IVF and embryo freezing really helps with because, again, it extends that timeline where, you know, people kind of advise you want to have like 18 months between pregnancies, right?

1:02:28And that's a lot of time. If you're trying to have a kid before 35, that ends up being super, super difficult. So I just wish that this set of imagination and investment in reproductive technology was way greater to help fix that cost versus benefit situation. Because when you think about artificial wombs, people only talk about it in the context of helping premature babies. And I think that that's obviously amazing. It's super sad that there's this critical window where this infant's lung can only breathe liquid and not air. And that's when most of these pre-meas are currently dying because incubators can only help you after that critical period of lung development.

1:03:12So it's cool, the idea that you can save more premature babies. But I think it should be in the public imagination that this would be an amazing engineering feat that would help liberate women, again, with this choice of, okay, yes, some people have those orgasmic births. let them have, you know, 20 babies. They love being pregnant. They love being pregnant. And that's an amazing experience. But for some people they have, you know, horrible, horrible, you know, pregnancies. Like, you know, 90 % of women have vaginal tearing, right? So people don't even talk about that. Like 90 % of women have vaginal tearing, right?

1:03:43They have levels of it. Okay. You know, you know, level one versus level two, level three, level four is like, you're literally tearing from your vagina to your sphincter, right? It's like that. All the way. Yeah. You just have one big hole. Yeah. And it's like, has to be sewn up and it's like, okay, I feel like, I feel like if men were going through that, they'd be like, yes, let's do artificial moves. And anyways, that's not to say, I mean, whatever. I mean, obviously, on cost, all of these women are super happy that they gave birth, and I'm not trying to, I mean, pregnancy and delivery is all beautiful, but I just wish that there was more energy and effort around this mission of, like, let's do artificial moves.

1:04:17Like, that's actually an amazing thing that we should bring to the world rather than all of this, like, there's just, I think there's way too much negativity around it, similarly to all the other reproductive technologies of like, this is an option that should be opened up for all these women who have, you know, really complex pregnancies? Or just again, like, why is it so stigmatized that, okay, like, that's just a lot to put your body through and, you know, you want to be a, you know, surfer or whatever it is that you, you know, it's difficult to be pregnant for. Like, that shouldn't be stigmatized either.

1:04:47Yeah, I think part of the concern, certainly for me when I hear about artificial wombs, is like, we barely are scratching the surface again of, the complexity going on within our bodies and information transfer. And presumably there is actually a lot of information going on being passed through the mother's belly into the child from just like the mother walking around and speaking and hearing the mother's voice. And presumably any artificial wombs to make sure that they capture that information are going to have, I don't know, it seems like we're a long way off from understanding that fully and making sure that we're not missing out on anything.

1:05:23So what are your timelines on where you think, well, A, do you think it would be possible to completely grow an embryo from IVF without ever having to be implanted into a human? A, do you think it's possible? Is it possible to capture all that information? And C, if so, what's the timelines? I think from a first principles perspective, I think that there's a lot of engineering problems, but there's nothing that seems obviously impossible about it. So I think it should be pursued with maximum effort. And I think to your point about all these different things about the interaction with the mother's body, super interesting, not enough science, not enough research going into it.

1:06:05And I think there's the positive and the negative, right? The positive is like, okay, they'll hear your voice and things like that. But I think also women today are under an enormous amount of stress, right? If you think about the cortisol levels of women today versus 50 years ago, that's probably not good for the baby, right? And then also cortisol - Scrolling social media. Yeah, I think - Seeing doom every day. Doom scrolling? Yeah, yeah. So I think cortisol levels and their interaction with pregnancies should be studied more. Maybe it's the case that an artificial womb could actually create a more optimal, like the most optimal environment for a pregnancy, right?

1:06:38Yeah, that's a good point. Think about all of our chemical exposures that we're exposed to. Maybe it's a kind of dystopian, right? Like maybe we should just, like we should be more chill, right? Like we should have, you know, more, you know, less chemicals in our life and we should push the world to that so that, you know, women can carry. But I guess it's more being practical. I think it's also just about epic goals that people are behind, right? Like the moon mission was this like epic goal that like all of humanity was like, that is just, it just captures your imagination. And it's like so cool.

1:07:03And you're like, wow, we can like be on another planet. Like, that's really cool. And, you know, I think, I wish that this was one of those things. It's like, wow, like women could have like way more babies and like the babies could be like super healthy and we could like make sure that like there's none of these, you know we learned kind of bit by bit all of these awful things that can happen during pregnancy right like fetal alcohol syndrome and there's all these unfortunately there's these drugs that women were taking that were causing horrible uh you know deformities and babies so it's like it's not that we haven't run that experiment on ourselves already it's just that what what can we learn to optimize it so that you know we could have you know the healthiest of like the most kids i know it's something that i think is super exciting again probably from like this selfish motivation of like, it's something that I would want.

1:07:45But it does require, you know, an enormous engineering effort. And I just think that we did that for something, I mean, to be clear, I love the moon mission. I think it's badass and I'm glad we did that. But like, what would be the impact of an artificial womb compared to going to the moon? I mean, the moon mission came up with all this amazing technology that we're using, but like the impact of an artificial womb on society would be like, I think it could solve population collapse. I mean, again, there's all these like societal factors as well. I don't want to like be like one hammer, technology solves all problems, but I think it would have a huge impact.

1:08:16I think a thing that people also miss is it comes in different levels, like how integrated the artificial wombs would be and then also how many people would use it. So like a counter argument similar with everyone's doing IVF and everyone's doing artificial wombs. It's like the world's not going to look like that. It's not going to be the case that 100 % use it. It's going to be 1%, then 2%, then 5%, and then you'll have some of them already use it for 10, 20, 30 years. and then you'll see how the children develop, whether they're developing healthy and you will have this feedback as well prior to integrating it further and further into society, right?

1:08:52With both technologies, I think. So the worry about as if we switch it on tomorrow and now we've totally missed that this crazy thing is all a byproduct of it, that's just not how anything is going to actually be integrated into our world, I think. I mean, that said, a thing that does reliably govern our world is incentives and economic incentives. And if it turns out that artificial wombs are just so much more economically efficient, even at a cost of the health of the people that then come out of it, there is that gradient that will then always have to be fought against. And I think we shouldn't underestimate that.

1:09:30Yeah. You know, the moloch problem, essentially. Or that the artificial womb children are now the super soldiers that kind of just run away with society because they're also just tweaked in a bunch of ways. Well, yeah, definitely. Those are real concerns, and I don't think it's... Yeah, I think, but that's what I also mean, is it comes in different levels, right? As you pointed out, right now we're already, if a baby is premature, then we put it into an environment which is akin to an artificial womb just for that certain stage of development. And we have, right now, our embryos are lying in a freezer, which is also like, well, that freezer is making up the womb where it would technically currently be.

1:10:24Also, does it not blow your minds that you guys have kids? You have embryos that are in suspended animation. Totally insane. Do you realize that there's been babies born that are like, they were frozen for like 30 years? Yeah, right. So they could be older than their parents in some definition, right? It's bizarre. If younger parents had them, then afterwards someone else would. Yeah, if you get 25 and just have a 30-plus year old embryo. I also think we should definitely study it. And I think a couple of years ago or so, the first mouse was brought to term in an artificial womb. As far as I know, they had the...

1:10:56I think it didn't get past at day 18. No, I think it actually came, or they were very close to it. But basically, there are two stages. Like the initial stage of just getting to blastocyst is easy, relatively easy, right? And then you have to put it in this environment where now the lungs, et cetera, need to develop. Yeah, I think that's Jacob Hanna's work. And I think, I should double check, but I'm pretty sure what happened is that it was transferred out of the mouse and into the artificial womb. So I think, but it was the longest ever. I think it was something like. They didn't quite reach the 20, 21 days, whatever.

1:11:30I think it was like 15 or 18 days. Basically, I think the part that's really hard is implantation, that part of basically how do you get the embryo and the... Placentas, actually. ...to combine. And I think what they were able to do is just... Because basically, we've been doing it from the other end of like, okay, what critical developmental stages can we mimic? And then that's the one that seems to be the hardest, is how do you get from the embryo to start growing? And I think just on that, I talked to him, And I think he said that something like 99 point some high digits afterwards as well, percent of the desired progress was the same as if it was in a womb up to that stage.

1:12:16Yeah. As if it was in a life womb. And the problem that I have as a question around that is, okay, with a mouse, we are not going to notice if it has some mental health issue that it developed necessarily, right? Where if we bring it to a human, there might be other things where like those didn't many, how many nines really matters in terms of similarity and other things, as Liv pointed out, that we may miss. But again, that's why I mentioned the point of like, it's kind of a gradual thing, how it would be implemented. And probably you start with people that don't have the option to otherwise carry a child and they don't want to do surrogacy or something.

1:12:55Do you know that there's literally uterus transplants? So there are women who get their current uterus transplanted out of them, okay? They get another woman's uterus transplanted into them. They're on immunosuppressants for like six months, okay? Then they do IVF. They have the embryo. They become pregnant, they carry a pregnancy for nine months, and then they have that uterus transplanted back out of them. What? That's how much some women want to get pregnant. Wait, back to the original person? No, okay, it doesn't go back. The other uteruses, yeah. So there's a lot of discarded uteruses and so on.

1:13:30And you can imagine that. But that is actually, that's birthed, I think, in the dozens of healthy babies. So that's what I'm saying. It's really on both sides. Because that woman, she could have chosen to find a surrogate. A surrogate could have carried that pregnancy. But some women really love and want that desire and connection to their child. And you could also imagine that the uterus that was implanted was missing some certain characteristics. So you actually artificially add a couple things. And then maybe you add a few more and a few more, and it's kind of like Theseus uterus. It's like, at that point, is it still artificial or natural?

1:14:07Who knows? Well, man, I'm going to get canceled for this one. But I think just getting off the point that you were making earlier about like, you know, if you open this door, then it can create all these like perverse incentives, right? Like you can even think about that from what's already happened, right? So for egg freezing, right? Some people, they're kind of more critical look at it as, okay, companies are offering this because they're just trying to like, you know, work you harder and all of, and like, you know, that's why they're doing it, right? And that's like, it's a nefarious motive, right?

1:14:30But like, I don't know how you would self-report your choice to do egg freezing or, you know? No, I did it entirely because I wanted to give myself optionality. So I would say the same, but I think you could imagine a society where women are pressured that, okay, you shouldn't have kids before you're 45 because you can, right? So it's sort of like, I don't know, I think the thing that's really critical that matters is like, does the person really self-report that there was their free choice? Or is it the case that they're getting pressured by society or their employer or their family or whatever?

1:14:57And I think that's really hard to measure, but I think at least I can hopefully self-report most of the time whether I think I'm being pressured into something or whether I'm doing it in my free will. Right, and again, throughout history, women have been pressured over their bodies and their fertility choices. Yes, constantly. It's a little unfair to just focus on this and ignore all the other pressures that have been passed down throughout history. And generally speaking, offering more options creates more choice, not less. And presently, I think, surveys show that women have fewer children than they would desire to have, in Western society at least.

1:15:37Yeah, and I think part of that is the secondary infertility. I think part of that is the, like, yeah, basically pressure on over-parenting of, like, competing with the Joneses with the amount of, you know, parental effort that's given. And I think the other thing that I think is really recently debunked was, you know, there's obsession with, like, breast is best, right? There's so many women for which breastfeeding is not fun, okay? It's like your nipples bleed and there's not enough milk. And it's like to pressure and make those women feel like they're somehow lesser or doing a bad job at being a mom, which is already like the hardest, most impossible job, is just so messed up.

1:16:07And now that they've like done so many more studies because this became such a meme and people are like obsessed with like, okay, breast milk is the best. You know, it's been debunked and it's like, okay, you know, the outcomes for children and for adults who, you know, varying amounts of like breast milk versus formula milk are, you know, very similar. And I think that, you know, we should always research and find out, you know, what truly is best. But I think in the absence of really having that definitively, you know, captured, it's really, I think it's really wrong to then stigmatize women for one choice over the other when it's like, it's just this situation for their body or for, you know, what makes them, you know, it doesn't have to be that you have this physical inability to breastfeed, right?

1:16:46For some women, it's an incredible amount of time. If you calculate the amount of time that people spend breastfeeding, I think it's like, I don't even know, it's something absurd. It's like six hours a day for an infant. And it's not six hours in a row. Women just don't find that fun, and that's okay. It's throughout the night. You get two hours sleep at most. And not great for the baby, either. You can have a grumpy, borderline-crazed mom because she hasn't slept. The thing that I think we only can find out empirically and that also matters around that is, okay so we have given ourselves optionality right but we'll never be able to run back the counterfactual of whether we would have had a child then at 37 versus how we are currently in a situation where probably going to have one at 41 when you're 41 or so right for the first time and and then we we won't ever know whether we would have had more in the we're pressured to do it or we are enabled to do it later.

1:17:42So I think that's one interesting thing, whether you know of any surveys there. And then the other one I'm also curious about, whether you know whether presently people who have been given the choice of sex have chosen one sex over the other statistically. Oh, those are both interesting questions. So yeah, I think one thing is that people, yeah, it's really hard to run the counterfactual, right? Because some people who have kids super young, they're like, oh my God, I love being a young parent and, you know, being young at their wedding and all the other things, right? But then, you know, they gave up all these, you know, being independent when they were young, right?

1:18:16So it's really hard. I don't think you can prescribe for one person one specific thing, right? For some people, it's going to be the great decision to have kids at, you know, 17 or 20 or whatever age. Like, that was, like, it really solidified them into adults. It gave them more responsibility. It got them on the right career path. It got them to, like, take their lives seriously. There's that story. There's also the other story of, like, you know, I really wanted to be, you know, independent until I was 30, 40. I mean, people having kids when they're 45 or 50, older than that as well. So it's like, again, I think it's like a super personal decision to like that individual, that couple, that time, what their ambitions are.

1:18:48Like there's certain ambitions that you have to do when you're young. There's certain ambitions that you can do when you're older. It really just depends on what matters to you in your life. And then for the sex selection stuff, in the US, there's actually a bias toward women or girls. And that's because of a number of factors. So one, people who are doing it, historically, we've had a really low-resolution understanding of genetic issues, right? So a lot of times, females are less likely to develop autism and a lot of these other psychiatric conditions that parents are trying to prevent. So in the absence of actually being able to quantify the risk, they'll just say, well, women, girls are less likely to have it.

1:19:27So that's one reason. How strong is it? Do you know the— I don't think it's very strong. I think it's a slight preference toward girls. I don't think it's super strong. And I think, similarly, that's probably why it was banned or censored in India and China, is that there's a really strong, unfortunate, I think, economic incentive. If you have a male child, that affords you a lot. Basically, the way that it is sometimes structured is that, okay, a female child is basically a net cost, and then a male child is a net gain. And that's, again, really screwed up that that society is structured that way where someone would literally, you know, kill a female child.

1:20:06But, you know, I think, you know, it makes sense in that context to censor that information for that reason. For that reason. And I think now that we have all this information, maybe we'll decide that certain information should be censored because of info hazard, right? There is this idea that certain information, maybe we wouldn't want to know the exact time and date of your death, right? There's some things that we're unpacking and finding out that maybe would contribute to that info hazard. Like some of our users, for example, they'll only want to know about pediatric conditions and not adult onset, right?

1:20:38Or they'll only want to know about things that affect their embryo, but they wouldn't want to know things that affect themselves, right? Because sometimes when you test your embryos, you can find out something about yourself. So all of these different combinations of like, I know maybe saying censorship sounds too negative, but basically of which information is going to be useful to you in this context versus not. Again, it should be an option. But I mean, maybe it's information overload, right? Like I hate when I go to the grocery store and there's like 70 different types of ketchup, you're just like, oh my God, come on, like just one.

1:21:04But I think the default in this category has been the opposite of just like one size fits all. You have to do it this way. you have to do it at this time. If you don't, you're going to be an outcast. And I just like that it's pushing a little bit in the other direction. So to finish up, what would your ideal 30 or 40 years into the future

1:21:27techno fertility world look like? And why is it a win-win in your mind? My dream would be that we can slash incidence rates for every major disease within a single generation or a few generations. And that's just fully off of the free choice of parents to mitigate risk for all of these diseases that we currently know about. So that's, I think, something super exciting, is that people freely choose to have the child that they're best equipped to take care of, where basically they thought through all the implications of having this specific kid, and they chose it, and they love it, and they take amazing care of it.

1:22:08So I would want that to happen. I would want, you know, artificial wombs to happen and that they're like safer and super optimum. And, you know, like they help people who want to have more kids have the ability to. But also at the same time, people aren't like pressured and feel like if they want to experience pregnancy, that they're somehow, you know, pressured into having it one way or the other. So yeah, basically a world that's less dogmatic, that's like super evidence and data focused on the things that we can measure, but also humble and acknowledging the things that can't be captured in data that could also be important, right?

1:22:41Like the emotional piece of it. So I think it's just sort of like, I would love, yeah, I don't know. I just would love people to basically accept both sides of it. There's an emotional side to it and there's a data side to it. And don't try to minimize either. Don't be arrogant, right? Just be humble about, hear all the things that we can learn. And yeah, you know, hopefully artificial wombs, embryo screening, and us living a lot longer too, right? So that we can spend more time with our kids. So there we go, folks. Thank you so much for tuning in and a huge thank you to Noor for taking the time to talk to us.

1:23:16Hopefully this was illuminating about, well, not only Igor and my personal life, but some of the technologies that are on the horizon for people who are prospective parents. As always, lots of links in the show notes. Hope you enjoy. Happy reading. And I'll see you next time.

1:23:36Thank you.