The Bioinformatics CRO Podcast

Transcript of Episode 21: Noor Siddiqui

Disclaimer: Transcripts may contain errors.

Grant Belgard: [00:00:00] Welcome to The Bioinformatics CRO Podcast. I’m Grant Belgard. And joining me today is Noor Siddiqui. Nora is the founder and CEO of Orchid. She was educated at Stanford and before that was a Thiel Fellow. So she’s our second Thiel Fellow on the podcast and started a company called Remedy. So Nora, welcome.

Noor Siddiqui: [00:00:22] Thanks so much for having me on Grant.

Grant Belgard: [00:00:23] Yeah. Thanks so much for joining us. So we always start with what are you doing now? Tell us about Orchid.

Noor Siddiqui: [00:00:29] Orchid helps couples have healthy babies. And the way that we do that is we’ve developed a new type of genetic test for couples who are planning on having a child soon. So we analyze both partners DNA and identify the disease risk that’s most likely to impact their future child’s health. So we look for the top diseases things like cancer, heart disease, schizophrenia, diabetes, conditions that really matter to future parents. And unlike most genetic tests, you can actually do something about the results you get from Orchid. So one of the options that we offer is an embryo report where you can quantify the level of genetic risk in each embryo so that couples can select the healthiest embryo to implant. So the high level mission of Orchid is we want to give parents peace of mind and give their children a better chance at a healthy life.

Grant Belgard: [00:01:08] Is this on the basis of polygenic risk scores?

Noor Siddiqui: [00:01:11] Yeah, that’s correct. So essentially, if you look at the types of pre-conception genetic testing that’s available today, those are carrier screens. So these are looking at super rare recessive monogenic conditions. If you look at human genetics, we have identified about 5000 single gene diseases. But collectively these 5000 diseases only affect about 1% of babies that are born. So in contrast to this major really incredible advance that’s happened in genomics that we’re excited to bring to market and bring to parents, is that now we can measure genetic susceptibility for the most common conditions. So things like heart disease, schizophrenia, diabetes, where a single disease has sometimes double digit prevalence in the US. So what we’re really excited about and we think is really important to offer to parents is that we shouldn’t really be discriminating based on the genetic architecture of a disease. So right now there are tests that allow you to measure risk for single gene diseases and that’s really positively impacted the lives of the rare disease community. But what about the vast majority of the rest of us? So genetics impacts risk for every major disease. And now we have this newfound ability to actually measure that risk because dataset sizes have now grown into the hundreds of thousands, sometimes millions of individuals where we actually have enough cases. So individuals with the disease to build these polygenic risk scores where there’s real predictive power behind them.

[00:02:26] So that’s a really major advance. And then on the other side, on the single cell sequencing side, we finally have a high enough fidelity sequence off of something as a small amount of DNA that’s present in an embryo to actually be able to mitigate that risk. So that’s exactly how Orchid designed our two products. So we have a couple report which just takes the saliva sample. It’s an at home patient initiated physician order test that allows couples to measure risk. So just quantify are we at normal or elevated risk for these conditions that everyone cares about? And if we are elevated, we can actually make a plan. So instead of it just being, oh, I found out some bad news about us. It’s actually actionable. You can make lifestyle changes. You can monitor your biometrics if you don’t want to go through IVF. But if you do want to meaningfully mitigate genetic susceptibility for your future child, it’s possible to go through IVF, create embryos, and we identify for you what the delta or relative risk reduction that you could achieve through creating embryos and identifying the one that’s at lowest risk. So we think that these are two significant scientific advances, and we don’t want them to just stay on the shelf like unfortunately a lot of technical advances do. And we think that this is a really high impact, valuable report and information to give to future parents.

Grant Belgard: [00:03:34] Do you additionally use information on family history?

Noor Siddiqui: [00:03:37] Yeah, absolutely. I think that family history is really important because right now genetic testing is unfortunately pretty nebulous. So if you have a really basic common question like, hey, my aunt has breast cancer, is that going to affect me? Right now, the panels are super small. There’s just a small number of these monogenic high impact variants that have been identified, but they don’t tell the whole story. So if you wanted to go investigate that right now using existing tests, you get a really inconclusive, unsatisfying answer, which is okay, it clearly runs in your family in the sense that, okay, we’ve identified multiple individuals who have the disease. But the panel that we have only looks at this very small fraction of high penetrant variants that don’t tell the whole story. So that’s why we’re really excited about polygenic risk scores is because it captures risk across the entire genome. It’s not like we’re just looking at a small fraction and a fraction of variance. We’re looking at literally millions of variants, which is what collectively drives risk for these diseases. So we know that if we provide these polygenic risk scores, these more advanced genetic susceptibility assessments, we’re going to identify a lot more people who are at higher risk that wouldn’t be captured on just a simple monogenic small panel type of test. That’s the type of information that I think parents deserve. I mean, why is it that we’re only telling this really small fraction of people about elevated risk when we already know that individuals who are in this highest 99, 98th percentile of a polygenic risk score are also at increased risk.

[00:04:57] So I also want to obviously put a disclaimer. This polygenic risk scores are really exciting, but we can’t capture 100% of disease risk. So if we identify you at normal genetic risk, that unfortunately isn’t a guarantee of a healthy life, that just means you’re an average genetic risk. These studies look at hundreds of thousands of individuals, and these scores capture a lot more variation than these panels do. But they don’t capture the sporadic non-genetic causes of the disease. And for these complex conditions, it’s not Down syndrome. We’re okay if you certainly have the condition. So we’re measuring genetic susceptibility, which is an important component of all disease risk. But unfortunately, we cannot guarantee that a child or an individual won’t get a disease simply because they’re at normal risk. And that’s something that we care a lot about in our reporting because this is a more advanced type of genetic testing. It’s not as simple as saying yes or no. You have this variant. It’s about measuring risk, which is a more complicated concept. And we care a lot about making sure that couples who are using this information to make a really big decision really understand what the results mean. And that’s why 100% of our results are physician ordered by an independent third party. This isn’t a pill farm. People are reviewing whether or not candidates are really going to benefit from our testing. And we also have a genetic counselor who provides personalized results, personal walkthrough for every single report.

[00:06:07] And he or she is also available synchronously for couples to really dig into the details the studies behind the results because yeah, I think that something that’s unfortunate about the way health care is practiced today is that I think that it’s a little bit paternalistic. I mean, you’ll see some folks in health care who see themselves more as gatekeepers than really as enablers. And I think that this generation of parents really wants to be proactive. They’re planners. They didn’t have children in their early 20s. They’re probably having them in their late 20s or early 30s, mid 30s, late 30s. And being planners by nature, you don’t want to take unnecessary risk. And that’s exactly what Orchid is trying to do, is we’re trying to say that your child’s health doesn’t have to be a genetic lottery where, okay, did you get lucky to not have all of these variants that could confer a risk? It’s actually, hey, identify risk early and take action, whatever action that makes sense for your family. For some families, it’s going to be lifestyle changes. It’s going to be monitoring biometrics. It’s going to be nutrition. But for some families, it is going to be mitigation through IVF. And I don’t think that there should be any finger wagging about that. Everyone’s individual decision about something as intimate and personal about as how they’re going to have a child is really up to them. And I don’t think it’s up to someone else to decide how people choose to have children.

Grant Belgard: [00:07:17] So talking about mitigation, there are certainly antidotes out there about people getting back genetic tests and making big lifestyle changes. But on balance, how frequent is that? I’m guessing that the people who would go out and do something like Orchid are probably a lot more likely than the average person to conscientiously do that. But I was just wondering, how often do you think people will really make hard lifestyle changes to their diet or exercise routine or try to get their family really in a better position for that?

Noor Siddiqui: [00:07:49] Yeah, I think that’s a really interesting question because I have two minds about it. So on the one hand, I think that behavior change is extremely hard and that’s why doing genetic testing is great for your future child, because getting people to lose weight, getting people to exercise, getting people to eat well is actually really, really hard. So if a couple or a parent can just say, Hey, look at birth, we’re not going to predispose you to these conditions versus people who are at really high genetic risk are having to play this uphill battle of it’s really difficult to basically invest in those lifestyle changes. So I have two minds about it. I think that at some level, you can’t force someone to make changes that they don’t want to make. And that’s, I think, what the uphill battle is. But I think that for people who are trying to optimize their health, then it’s going to multiply their efforts. If you’re invested in healthy aging and wanting to understand where your risk is and some changes are easier than others. So sometimes losing 50 pounds maybe sounds a lot more difficult than maybe just wearing an Apple Watch and monitoring your AFib that way. It’s like passive monitoring sometimes is an easier intervention than drastically reducing your weight.

[00:08:56] So I think it really depends on the disease. It really depends on the couple. It really depends on the risk that they’re trying to mitigate. So unfortunately for a disease like schizophrenia, there’s really not much known about how to treat or mitigate that disease. But for something else like type I diabetes, just simply knowing that you are high risk gets you on a speedier diagnostic pathway. A lot of people, I have personal friends who found out that they were diagnosed with type I diabetes in their mid-thirties. All of their teens, all of their 20s, they were extremely lethargic, just thought that was a normal part of life and just was misdiagnosed and found out far later than they should have what the actual root cause was. So I think that just understanding that risk early can sometimes just avoid a diagnostic odyssey to find out what the true cause is. Fortunately, I hope that wasn’t a non-answer. But I think that the answer is super variable depending on the disease, the individual and exactly what types of actions that would be seamless to integrate into their lives. Just a one time purchase to monitor biometrics as opposed to, okay, this is a sincere daily investment. Okay, I’m going to change my activity level or what I’m eating.

Grant Belgard: [00:09:58] That’s a good point. Like more passive AFib monitoring is a much lighter lift than going on a low salt diet or something.

Noor Siddiqui: [00:10:06] Yeah.

Grant Belgard: [00:10:08] So the dynamic range for polygenic risk scores for a number of phenotypes of interest is quite large and would certainly be actionable. How does that look for children of two parents?

Noor Siddiqui: [00:10:23] Yeah. This question that you’re asking was actually the entire motivation for the product, because we had initially just started on, let’s just offer embryo reports to couples who are already going through IVF. And then there was so much interest from couples outside of IVF saying, we have a sibling or a parent with schizophrenia. We’re super afraid. We’re just choosing not to have children because we don’t know that any mitigation is possible. And they didn’t want to take the step of doing IVF without any assurance or idea of, okay, how much could I actually mitigate risk for this disease. So that’s the entire motivation behind the couple report, is to actually identify and measure risk early and to show for a specific couple, because unfortunately, there’s not one answer for, okay, this is a relative risk reduction that’s possible for every couple. It’s very, very specific to what are the genetics of the two people that are involved to be able to make that assessment. But that’s exactly what’s included in the couple report. It tells you just red light, green light, are you at normal or elevated, is your future child going to be at normal or elevated risk for any of these conditions. And then in addition to that, if elevated risk is identified in a future child, we show what the range of outcomes would be given, a thousand simulations that we run our model of how the couple’s DNA could recombine.

[00:11:29] We show, okay, this is the 20th percentile, This is the 80th percentile. So we’re not saying, okay, in a crazy world where you have 1000 embryos, we know that that’s not possible in a world where you produce between 4 and 10 embryos, which is pretty conventional right now for folks who are going through IVF. What would that lowest risk versus highest risk embryo be so that a couple has some idea of what the range of risk for their children would? I’m sure your audience is pretty technically sophisticated on the genetics side, but I also find it really funny if you ask the average person, how genetically similar are you and your siblings? They’ll give you really crazy answers. First they’ll say 100%, and then I’ll say, Wait, but then what are twins? And then they’ll say, Oh, okay, wait, no, no, no. Let me see. So basically just to for folks who don’t know, siblings share 50% of the DNA. So you can think that, okay, there is necessarily going to be variance between the genetic risk for each of these embryos. And we’re just quantifying that.

[00:12:18] So you can obviously see that where these risk scores and these simulations have been validated in using empirical data. So you can see a sibling who has a high PRS, What was the rate that they got a specific disease as opposed to other siblings who have a lower PRS score. They get the disease at lower rates. That’s the entire point. It’s just a statistical model of, okay, these variants are associated with higher rates of disease as opposed to these variants are associated with lower rates of the disease. The succinct answer to the question is the amount of risk reduction that’s possible through embryo prioritization varies enormously between couples. It depends on the genetic architecture. So meaning the number of variants that are included in a polygenic risk score for a specific disease. So the entire point of the couple report is to give couples a concrete idea based on your specific genetics, based on the specific disease that you’re concerned about, how much mitigation, how much of a risk reduction would be possible were you two to elect to go through IVF, create embryos and prioritize the one that’s at lowest risk.

Grant Belgard: [00:13:12] I guess another challenge in human genetics, this is something that we’ve run into at the CRO before is human genetic samples tend to be overwhelmingly of European descent.

Noor Siddiqui: [00:13:23] Yeah.

Grant Belgard: [00:13:23] And so the large data sets that are available for building polygenic risk scores tend to be incomplete. So how does Orchid deal with that? And obviously that’s something that is changing over time. But I imagine for a lot of indications of interest, you don’t have probably good weightings for global populations.

Noor Siddiqui: [00:13:42] Yeah, thanks for pointing that out. That’s like one of the biggest tragedies, unfortunately, of genomics during this time. The fact that overwhelmingly the data sets just are predominantly European samples, and that means that the performance there is better than for other ancestries where there’s less data available. So unfortunately this is of course, as everyone understands not a problem that Orchid can tackle alone. But I think what’s really exciting is seeing the entire global genomics community getting behind this. There’s a large consortia who are spending millions, sometimes hundreds of millions of dollars on making sure that we’re aggregating and biobanking more diverse samples. And that’s obviously something that Orchid can support in part, but it’s something that the entire genetics community has to get around. And worse, obviously frankly disappointed to date that the sample set is so biased. But in terms of how we specifically can combat, we combat that. It’s primarily in software. So looking at techniques around local ancestry and friends where basically we can leverage the fact that there is shared haplotypes or shared genetic structure between ancestries in order to boost performance. There’s different techniques like that that we can use to make the scores as performant as possible given the limitations. But we unfortunately can’t be responsible for the shortcomings of the entire genomics community. But we’re 100% behind getting more diverse samples. And that’s something that’s critical not just to our efforts, but to making genomic medicine and precision medicine affect everyone’s lives and not just one ancestry group.

Grant Belgard: [00:15:03] It’s really interesting. I would imagine, launching a company like this about which essentially so much sci-fi has been written, but really the technology is now available. And obviously, one of the things that some of those novels explore is questions around access, for example. Do you expect and obviously this will be a rapidly shifting landscape. So the answer in the next few years may be quite different from the answer a decade from now. But do you anticipate something like this could be eventually covered by health insurance companies, by potentially national health services and so on?

Noor Siddiqui: [00:15:36] Yeah, absolutely. I think that accessibility is the number one priority for Orchid. We want every couple to be able to have a healthy baby. That’s the stated mission of the company. And I think that right now what’s happening is that couples who are at high genetic risk have sometimes no mitigation option right there. Their only mitigation option that’s provided is, oh you should adopt a child or not have a child. And that’s extremely sad and it shouldn’t be that way. So we’re building the tool so that every couple can have a healthy baby. So we’re obviously doing that on the technology side, but on the accessibility side, that matters an immense amount to us. Our impact is limited by unfortunately the people who can afford the technology and that’s unfair. So we think that insurance companies, lawyers, everyone should be willing to to cover this, because having a family should be a human right. Everyone should be able to have a healthy child. It shouldn’t be the case that, okay, some people have to play the genetic lottery in order to just see, okay, are we going to roll the dice and be lucky enough to have a healthy child or do we have the opportunity to actually assess risk up front and then mitigate it if it’s available. So we actually have a low cost application program that folks can apply to for people who aren’t able to afford the sticker price of the service.

[00:16:45] But of course, we’re advocating to make sure that every insurance company, every employer, every fertility benefits program offers our product because we think that every couple that stands to benefit from this should have the opportunity. It shouldn’t be about what their financial situation is, that shouldn’t be the limiting factor for their ability to get on board. I think that unfortunately it’s sad in the US, we’re in this situation where there’s not uniform IVF coverage. So 15% of folks are infertile. So we think that IVF has this really incredible history where since 1990s, IVF has been preventing the diseases, the monogenic diseases, that gene therapy will only one day treat for only $20,000 a case. And you look at stuff like Luxturna that treats a very rare degenerative eye condition through gene therapy. It costs $840,000 per eye. So we’re talking about $2 million compared to $20,000 if you’re able to go through IVF. So IVF has this really incredible technology that allows people with infertility to have babies as well as people who want to mitigate disease to have healthy babies. And I think that it’s really unfortunate that in the US, we don’t prioritize building families as much as we do in other countries.

[00:17:52] So if you look at other countries like Israel, they have free IVF until you’re 44. That’s just a different model than the US where it’s like, okay, well some people who have the financial means are able to afford IVF. And we don’t mandate that it’s covered by insurance. And I think that is something just forecasting I think will change because I think the demand for these services is already on the rise because people are choosing to have families later and that naturally means there’s going to be a higher rate of folks who need IVF. And I think that the other reason companies like Orchid, where it’s not just about infertility, it’s also about disease mitigation. They’re just going to be a rising demand for coverage for this. And I think that that’s something that every American deserves. That’s something globally that folks deserve. Yeah, It’s unfortunately again not up to Orchid what insurance companies and other folks decide. But from our perspective, having a baby is one of the most consequential moments in your life. And being able to mitigate disease risk is obviously a really important part of that picture.

[00:18:44] Outside of insurance companies, there are a lot of really exciting technologies that are coming down the pipe to make IVF more accessible on the automation side. So I don’t want it to sound too much like a dream, but the idea of making IVF a little bit more like Lasik, where there’s a repeatable process and performance ranges that are expected versus right now the situation is that there’s certain centers of excellence where they’ve had thousands and thousands of cycles and they’ve been able to do enough reps where their performance is really solid as opposed to sometimes these smaller clinics who just don’t have the volume. Their staff doesn’t have the training, being able to use automation to level the playing field so that more centers can serve more folks at a lower price point. Fortunately, I think there are some companies playing in that space who should also be soon will be able to alleviate some strain on demand there. But it’s going to be a process just like any other technology curve. If you look at Tesla, I started out with super expensive sports car and then now, several years later, they’ve come out with many other product lines that are increasingly more affordable and address the audience beyond the sports car enthusiast.

Grant Belgard: [00:19:45] Orchid is, of course, focused on disease risk mitigation, which I think maybe outside of finger wagging bioethicists and things, most people would totally be on board with that. But of course, the technology can be used to look at weight, height, IQ. Things that parents would want for their own kids. But obviously there are other concerns around. Given that the technology is out there, genotyping is relatively inexpensive and so on. Not that Orchid would do it, but basically do you think that is 30 years from now that that will basically be either the norm or outlawed one or the other? It seems like one of those things that the tech enables it. Obviously, many individual parents are going to want it for their own kids well, that genie be out of the bottle.

Noor Siddiqui: [00:20:35] Yeah. In terms of Orchid, we’re squarely focused on disease mitigation and we think that that provides an enormous amount of value to parents. Specifically, if you’re looking at these highest percentiles of 98, 99th percentile of a distribution, you’re at 2x, 3x, 4x, 5x, sometimes 10x, the risk for a disease I think that’s merited. It’s if you’re in such a high risk category and you want to move your child into normal risk, I think that society and clinicians are sympathetic to that. And to be honest, we’re already doing that for a disease of a different genetic architecture. We’re already doing that for folks with cystic fibrosis and other conditions where it’s been identified that the couple is high risk and now let’s mitigate it via embryo prioritization. So I think that that’s something that’s squarely where the science is solid. And I think that for a lot of these other traits, things like height or intelligence, there’s been a bunch of papers published that just show that there’s just not very much variance. You’re talking about something like two centimeters for height and you’re talking about something like less than 3 IQ points, maybe 2 IQ points for IQ. So I think that that’s just not really a significant difference. It’s not really merited to try and prioritize your embryos based on something that small as opposed to if you’re talking about, okay our child is going to be at 3x risk for schizophrenia as opposed to 1x risk. And we’ve also have a documented family history. I think that that’s a much clearer indication for a positive result that’s going to occur as opposed to for something frivolous, these traits that society clinicians are just not going to be on board with that type of use of the technology.

[00:22:04] So I think that there’s always going to be heart surgery and there’s going to be plastic surgery. So Orchid is squarely in the heart surgery range. I don’t know what other companies are going to do. Maybe they’re going to be in the plastic surgery or something even shadier than plastic surgery type of range. But fortunately, we have regulations like GINA. So what GINA does is it makes it so that you can’t discriminate someone based on their genetics. So I think we already have a regulatory and legal background behind, okay, if there’s sufficient damage that could be caused by the use of a certain technology. So for example, I think we all agree that you shouldn’t be discriminated from your insurance or your job based on your genetics. So in order to ensure that, we pass something like GINA. So I think that similarly, if there’s sufficient interest or sufficient number of bad actors in this space, I think that regulation will emerge to combat that. I think that what’s really important is to just stay close to the science, stay focused to where predictions are actually meaningful and affect quality of life. And that’s what Orchid’s focus is and whether or not other players will choose to be less conservative, humble and honest about where the state of the science is. I can’t really yeah, I don’t know. I can’t really forecast what other folks will do.

Grant Belgard: [00:23:12] Okay. Thank you. I think your path has been especially interesting. I think anyone who’s gutsy enough to skip the traditional route, especially when the Thiel Fellowship was quite early is somewhat I’m keen to talk to you and learn about their thought process. Can you tell us about from the beginning, what brought you here?

Noor Siddiqui: [00:23:35] Sure. I think I have a maybe weird path. I think when I was in high school and I was applying to colleges and also to the Fellowship, everyone thought it was a crazy idea and couldn’t be making a worse decision than to do the Fellowship. And then after I did the Fellowship, I chose to go to college. And then again everyone said, This is crazy. Stop working on this company that’s going super well and instead to choose to go to college. So I think basically what I’ve gotten used to throughout my entire life is doing things even when other people think it’s a terrible idea, because I think that at the end of the day, it just comes down to how you’re feeling specifically at the time. Sometimes on average, a decision makes sense for the average person, but you’re not an average person. You’re a specific person and you have specific goals. So for me, the Fellowship couldn’t have been a better decision. I learned super early what it takes to start a company, to build a product, to raise money, to build a team, to sell into health care. I would have wasted probably more than a decade working in consulting or working at ten other different types of companies to get that same experience and just a few years and super early in my life.

[00:24:41] And I think that that totally changed the trajectory of what I was interested in at Stanford. So I spent almost 100% of my time doing research because, I was like what’s really exciting about being an academic institution is being at the cutting edge of research. This is something that you don’t have the opportunity to do anywhere else. These are datasets that sometimes are academic only access that you don’t you aren’t able to access commercially. So basically my time during the Thiel Fellowship completely changed the trajectory of my life, specifically even what I chose to focus on while I was at Stanford. And then I think after Stanford, the decision to start Orchid was actually premeditated almost a decade prior. So when I first started the Thiel Fellowship, I actually really wanted to work on something similar to what Orchid was doing, but I just didn’t feel like I had spent enough time in the industry, spent enough time with the research to really be able to take it head on. I think the other thing that I really learned from the Fellowship is that starting a company is extremely hard and you can only do it if it’s something that your heart is really in, where this is something that you want to be, your life’s work. This is something, this is a hill that you want to die on. And I always knew that it was the reproductive tech space. That’s where my heart was.

[00:25:46] I felt really fortunate to be able to come on a decade later, be actually in the position where I felt like I’d had the requisite experience to actually go do my life’s work, go do the thing that my heart was truly in, which is what Orchid is doing now. I don’t think that there’s any higher calling for me than helping couples to have healthy babies and bringing the team together on both the computational chemistry and molecular bio side in order to fulfill that vision. And I think that this is a particularly sensitive space where it’s not just about does this get done, but does this get done. That’s really the key component. And I think that that’s like operating at the highest scientific and ethical integrity is really core to Orchid’s mission. And I think that unfortunately, it’s not core to other companies. And I think specifically it’s funny. I think that some people see that as, oh, it’s like an extra thing to take on. But I think that the company that’s going to be most successful in this space by definition, in my opinion, has to have both the scientific and ethics really close to their heart, because I think that that’s ultimately what the public cares the most about. Of course, everyone’s sympathetic to the idea of mitigating disease risk, but is this a company that you can truly trust that is really conservative and humble and thoughtful about the actual deployment of these polygenic risk scores. We know the science is there, but how do you actually communicate that science in a way that’s comfortable and credible both to physicians and patients? And that’s really core to our mission.

[00:27:11] Surprisingly, I think it is going to end up bearing out as a strength because I think that’s ultimately what the public and physicians care the most about, is not trying to take the science too far, focusing on where do we really know that we can mitigate risk and just being open and honest about the limitations of things that we can’t predict yet, just that couples are aware of, Okay, if you have normal genetic risk, that doesn’t mean you have a guarantee of a healthy life. It means your genetics aren’t predisposing you to a condition. And similarly if you have elevated genetic risk, that’s not a guarantee. It’s not a diagnosis of disease. It means that you’re two fold, three fold, four fold, five fold depending on the disease, elevated predisposition or elevated likelihood of developing it. And I think that that’s just super important to drill into couples minds because these are big decisions and they should be properly informed about what their results actually mean.

Grant Belgard: [00:27:56] I guess this is the role of genetic counselors, but most people seem not to have a very intuitive interpretation of risk.

Noor Siddiqui: [00:28:05] Sure. Yeah. I think that genetic counselors are amazing and incredible, but I don’t think it’s actually just about them. I think it’s also about not cutting corners, not saying, hey, we’re going to do genotyping instead of whole genome sequencing. It’s about really characterizing the molecular biology of, okay, what’s the fidelity, how much coverage do we have for this particular region, how much does this region contribute to this score? So I think it’s everything from the chemistry to, okay, how are you vetting the specific PRSs that you’re using, which ancestry population are you using? How large was the training set? How large was the validation set? How many studies have actually reproduced this PRS score? What is the functional validation for the variance in the score? So I think that it’s actually full stack. I think that developing a product that really meaningfully estimates risk is actually a full stack problem. I would not say that our plan is to just shove this whole genetic counselors, hey, we know these results are super complicated, trying to explain to them like we’re full stack focused on everything from evaluating the variants to building the appropriate models to actually designing the reports. And then, of course genetic counselors and physicians are a piece of it. But I wouldn’t say that they’re being thrown a problem that hasn’t been really thoroughly investigated. And we’ve already taken it through with a very fine tooth comb to make sure what they’re getting is the most important insights to communicate to the couple.

Grant Belgard: [00:29:16] Great. So going back to the Thiel Fellowship, I asked the same question of Delian, but I would love to hear your response. What do you think differentiates the participants who thrived from those who didn’t?

Noor Siddiqui: [00:29:29] I actually think that this delineation of thrive versus not thrive is actually unfair. So if someone “didn’t thrive over a two year period”, I think that that’s not really the right timescale to evaluate what the impact of the experience was for them. So you can think about something like a PhD. You’re at least in the US, it’s about five years and you’re given a very loose mandate of what you need to do and a lot of ambiguity and a lot of figuring it out yourself. Sometimes people really struggle, really, really, truly struggle in their PhD. They need a lot of hand-holding and they need a lot of support from their PI. But then they come out of it and they’re incredible postdocs or they’re incredible junior faculty. And it was that that experience, those five years of struggling, failing and completely languishing and maybe getting nothing done for two years that actually allowed them to build this muscle that didn’t exist for them before. So I guess to give a more concrete answer, I think that sometimes the people who, “languish” or didn’t thrive for those two years might actually have the most outsized impact later because they basically realized, hey, I was on this super tracked path before where there wasn’t any ambiguity.

[00:31:07] I was always just trying to get the highest SAT score or the highest grade or something very specific and concrete. And then when I was thrown into an environment where I had to define my own objectives, that was disorienting for them. So maybe for those people, they actually benefited the most. Maybe they’re actually thriving the most from actually having gone through that exercise. But I think if you want to look at very conventional measures of success or thriving, I think that people who already had spent a lot of unstructured time and knew how to structure it and knew how to build software products or something where you have a very short timescale for it to be successful. The iteration time for a software product is much shorter than an iteration time for a biotech product where you have to do clinical trials, where you have to get IRBs on board. It just very different. I think the characteristics of someone who can be successful in a two year time scale is probably someone who’s just working on a small software product, who’s already had experience with shipping those types of products to users before. But I think that’s basically a very narrow and incorrect way of thinking about what the actual value of the experience is. I think that the actual value of the experience is just taking anyone who’s just high potential, really ambitious and then forcing them to do the hard work of figuring out, okay, you can do anything you want, how should you actually spend your time? And I think that it’s funny. People who are 50, 60, 40, any decade actually haven’t done that. They haven’t actually done the exercise of, okay, if I could work on anything, what should I actually work on, what is actually the best use of my time, What’s actually the best for society, What is like the highest leverage thing I could do? And I think that regardless of who you are and regardless the amount of time that you spend suffering with that question, it’s actually super valuable. But maybe that was too philosophical of a response that you were looking for. What did Delian say?

Grant Belgard: [00:32:47] So the crux of it was essentially the same. The ownership they took in an unstructured environment, the interpretation of that was quite different. So to what extent do you think something like the Thiel Fellowship could scale? Should something like that scale? Should other philanthropists come in and offer kids $100,000 to go do something other than college? What are your thoughts?

Noor Siddiqui: [00:33:12] Honestly, if you’re going to ask me where should philanthropy be directed, I think that it should be directed to reproductive technology. I think that reproductive technology is one of the most underhyped underfunded spaces. So historically, IVF has actually never been funded by the government. Any human embryo research isn’t funded by the government. If I were to be able to just direct a huge amount of philanthropic funds, I would say that there’s huge amount of work to be done in automating IVF and making it more accessible to everyone. There’s a huge amount of work that can be done on cutting edge technology, something like IVG, in vitro gametogenesis or the idea of taking a skin cell, taking a fibroblast and being able to direct it not only to become a stem cell, but after it’s been directed to a stem cell, which is already been discovered through Yamanaka factors, the ability to take an arbitrary cell and convert it into a stem cell. But actually, once you have that stem cell, can you go and convert that into an egg cell? So basically, the biggest limitation for women’s fertility window is the fact that egg quality declines with age. So if you’re able to make IVF fully noninvasive and create an arbitrary number of eggs at any age, that would really expand the number of women and couples that could conceive.

[00:34:15] And for some of these other conditions where specific couple, that’s very rare for them to be able to have a child that’s low risk being able to create more embryos for that more eggs and more embryos for that couple allows them to have a better chance of being able to mitigate risk. I think IVG, for example, so the ability to create an egg cell from a skin cell is something that a scientists are working on. There’s probably about five labs in the world that are doing work related to that. And I think that they’re underfunded. I would love it if they got more funding. I think that if you look at premature births, we made an enormous amount of progress with incubators. So there’s this idea of mechanical ventilation being able to support infants that are born at up to 30 weeks. And previously all of those infants died. But now we’re reaching this limit of 28 to 25 weeks where the 80% of these 200,000 plus premature births that are occurring in the US at this 25 to 28 week mark are all dying because they can’t survive outside of the womb. And why aren’t we working on an extra uterine system to support those premature babies?

[00:35:11] We’ve basically reached this limit of of our technology. And why aren’t we working on new types of incubators that could support those premature infants? That’s the type of technology that I would love to see. I love all this work that’s going into pharma, like developing new drugs for folks. Gene therapy is really exciting. A lot of this research is super exciting, but if I were to identify a single area that’s underfunded, where there’s a huge outsized impact for humanity and for the next generation, I would say it’s reproductive technology. So being able to help more couples have healthy babies that currently are just stuck because of essentially being unlucky, a premature birth. We don’t know what causes it. It’s just unlucky that child doesn’t get to live because we aren’t able to help it thrive outside of the uterine environment. So I’d love to see more people working on that. And there are scientists who want to, but they’re just underfunded because for whatever reason, we decided to direct our funds elsewhere. So maybe that wasn’t really quite what you’re trying to get at. But that’s the stuff that I’m most excited about.

Grant Belgard: [00:36:09] Great. Well, thank you so much for coming on today Noor. It was really interesting.

Noor Siddiqui: [00:36:13] Yeah, it was awesome to meet you Grant. And you’re clearly very deep on the science. You really understand what we’re working on. It’s always great to talk to someone so well-versed in genetics and even more niche topic of polygenic risk scores. So it was really great to get a chance to chat with you.

Grant Belgard: [00:36:24] Likewise.