30: Noor Siddiqui — Predicting Your Future Child’s Health Just Got Easier
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Alice Lloyd George: I’m excited to have Noor Siddiqui here today. She is the founder and CEO of Orchid, a company that supplies genetic testing kits and guidance to prospective parents who want to know more about the health risks that they may pass on to their children. Orchid just announced a $4.5 million round of financing. Congrats and welcome to the podcast.
Noor Siddiqui: Thanks for having me.
ALG: I was excited to see on Twitter, as soon as this announcement came out, everyone tweeting about it. You have a serious fan club in Silicon Valley of important people. And a bunch of mutual friends are involved — shoutout to Balaji, Village Global, Celestine from Boom, Devon Zuegel.
NS: I mean our friends are cool and it was cool to find out that we love all the same people.
ALG: It’s a backslap for ourselves. For having great friends.
NS: Exactly haha.
ALG: Let’s rewind to the beginning — before Orchid you were a Thiel fellow, you taught a crypto class at Stanford, did AI & genomics research with Sebastian Thrun, and got an MS/BS in computer science from Stanford. Tell me about this path and how you got this incredible resume.
NS: I’ve been following my interests from a super young age. It’s kind of funny. Orchid is only a one year old company, but it’s more than a decade in the making. This idea of helping couples have healthy babies and understand their genetic risk is something that I’ve been interested in since middle school. So it’s an honor to be able to get to work on this. And as you mentioned, be able to work on it with some of the most brilliant folks in Silicon Valley, folks like Balaji, who built Counsyl, which expanded carrier screening for couples. He shifted genetic testing from just this small set of rare mutations to a much larger set. When that was introduced it was considered crazy to test all of these things before pregnancy. Then he made that the standard of care over the next decade. So he’s an incredible person to have on board because he understands how the Overton Window shifts and how testing changes in medicine.
ALG: He’s an incredible person. I had the pleasure to work with Balaji when he was running Earn, I was on the board there. He can do every job at a company and run circles around everyone. It’s incredible to be with someone like that in a work capacity. On a personal level, I have an epileptic brother who is handicapped. So this mission is close to my heart. I’m also an investor in a company in New York called Kindbody that does egg freezing and IVF.
NS: Yeah, Gina is amazing. Good investment choice!
ALG: Gina is a powerhouse.
NS: I met her in person briefly before COVID at this conference. Back when we used to see each other in person. I was super impressed with her. So good choice.
ALG: On a personal level, you’ve talked in the past about how your family was part of the inspiration for building Orchid. Can you get into that.
NS: Sure. Unfortunately it’s a bit of a sob story. I grew up watching my mom go blind. She has a rare degenerative retinal disease. It was devastating to watch. People think I’m stubborn, strong willed, but my mom is 100 x compared to me. So she was unwilling to admit that she had this condition. She was unwilling to admit that it was progressing. And there was a series of car accidents. There were all of these crazy car accidents. We would say, hey, were you able to see what was going on? And she would deny it. Eventually it became clear that she shouldn’t drive anymore. It feels dramatically unfair — why do the rest of us get to enjoy our health well into old age? Then for other people, through no cause of their own, they end up getting sidelined in their life, hijacked by a program that’s running inside them that decides to take control of their life. Why is it that this idea might be controversial? This idea of genetic privilege. Some people get to grow up and not worry about these diseases. For other people the number one thing that’s affecting their life is a condition that they’ve been diagnosed with. It’s a chronic condition. It doesn’t have a cure. In the best case you’re committed to a drug for life. To the extent that in the future, parents can understand what genetic risks they carry, what genetic risks their future child will inherit and the ability to understand and mitigate that risk is a mission that will continue to motivate me. It was something important to me.
Building a company is hard and starting Orchid was something that will maintain my interest. Helping couples go into the most consequential moment of their life of having a child with all the information — that’s something that I personally want. That ‘why’ about the product.
My story is also, unfortunately, not very unique. Over one hundred million Americans are living with a chronic disease. It’s not a rare scenario. Different families are different levels of transparent about disease. It’s shockingly common for folks to disguise disease and to not talk about it because it’s something that’s difficult. Families often try to shield each other from it. But we should be talking about it. There shouldn’t be so much stigma and we should do what we can to mitigate those risks. The story that I think is funny is from the movie [The Farewell]. It’s about a Chinese family. Their grandmother is diagnosed with a disease, and the cultural choice is not to tell her, but instead to tell her family. It’s interesting that the burden of the diagnosis can be greater than the disease itself.
ALG: Interesting. Culture plays a big role in this. I’m sure you’re focused on the U.S. right now, but the way that we handle genetic diagnosis and attitudes towards fertility are so different country to country and culture to culture, right?
That said, it’s hard to imagine that we won’t live in a world a hundred years where everyone is pre-screened before being born. Unless they’re the product of anti-vaxxer anti-genetic testing types. But at this moment in time, there’s still a cost factor. Can you explain what the cost structure is? I imagine the reason you’re doing this now is that the cost of sequencing a genome has come way down. So why isn’t everyone doing this before having children?
NS: It’s something we thought a lot about. The goal of the couple report is to make it as accessible as possible to everyone. The other side of the product is embryo testing — being able to identify the propensity for each embryo during an IVF cycle, their predisposition to some of the most common diseases — things like heart disease, cancer, schizophrenia, diabetes. IVF in the U.S. is currently an expensive and time-consuming process. But to the extent that upstream of having a child, before a couple is pregnant, that they can understand what their genetic risks are — that’s the goal of the couple report. And it’s significantly cheaper than IVF or embryo testing.
ALG: So the product at the moment is the saliva-based test at home, before anyone’s pregnant. And the later product will be embryo testing, which is more expensive.
NS: Exactly. The couple report gives you your own genetic risks and also gives you an estimate of what your future child’s risks are. When you have a child, the DNA of both partners recombine. It’s funny when you ask people how genetically similar siblings are, some people will say 100%. So then what are twins? Siblings share 50 percent of their DNA with each other. There’s quite a bit of difference between each sibling’s propensity to disease. You can see that visually, right? Two sibling boys won’t be the same height.
It works the same for genetic susceptibility to disease. We like to show parents — the vast majority of couples — that they are at normal genetic risk for every condition that we’re testing for. But for some fraction of couples, they’re going to discover that they’re at elevated risk. Their children are going to be in that higher risk range. Maybe the 98th percentile for some of these diseases. That doesn’t mean they have to go do IVF. It’s just one of many options that they can think about for actively managing the health of their family in their pregnancy.
ALG: Compared to existing offerings, when a couple goes in and they’re going through pre-pregnancy or early fertility, they only analyze a small percent of DNA, whereas you are looking at all three billion bases. What’s the difference with the legacy system?
NS: You can think of it as old school genetics versus modern genetics. Balaji’s company Counsyl made mainstream the idea of carrier screening. Carrier screening is looking at Mendelian diseases or monogenic single gene diseases. Formerly, genetics was limited by small dataset sizes. If you have a small dataset size, you can’t discover susceptibility to disease where there’s millions of variants that are collectively driving risk. What you can discover are things like cystic fibrosis, Huntington’s, diseases where there’s a single gene cause. That’s the main difference. Old school genetic testing that’s available today is looking at these rare single gene genetic changes for diseases like cystic fibrosis.
In contrast, Orchid focuses on polygenic or multifactorial diseases — heart disease, schizophrenia, diabetes. These aren’t driven by one gene. They’re driven by millions of genes that collectively confer a risk for the disease. Genetic risk is different than a genetic diagnosis. If you have the gene for cystic fibrosis, then you have the disease. What we’re interested in is quantifying genetic susceptibility. So what is your predisposition to heart disease? People who are in the 99th percentile risk of heart disease could be four or five times more likely than the average to develop the disease. That’s the major difference. Yes, we are doing whole genome sequencing. We’re evaluating the entire genome. But the other main distinction is the actual diseases that we’re looking at and what the genetic architecture is thet drives risk for those diseases. Does that make sense?
ALG: That makes total sense. It’s definitive carrier screening for a few recessive traits versus the probability of a combinatorial genome disease.
NS: Exactly. Carrier screening is amazing. It’s great that people are doing that, but it affects a small fraction of people because they’re looking at fundamentally rare variants. Less than one percent of babies born are affected by these diseases.
In contrast, 100 million Americans are living with these other chronic diseases. We think it matters more to understand what is your genetic susceptibility for these diseases that are way more likely to affect you. There’s this other information that’s come online over the last three years, because we now have many hundreds of thousands of individuals that have been sequenced. We’re able to build these models that stratify risk for these diseases that are much more complex and that affect a lot more people.
ALG: I know this is a crude analogy, but say everyone was doing the Orchid tests and had that data on their phone even before they’re with a partner. There’s an app in Iceland that taps into a database of who everyone is descended from, because they’re all descended from 9th century Viking settlers and it’s a small population. They can bump their phones and see if they’re related — essentially an incest alarm that notifies the user if they’re too closely related. That doesn’t mean you can’t have kids, but it’s a number, something to factor in. In many years, if everyone had their genome sequenced, you’d have more data at your fingertips to do something like that, right.
NS: It’s funny, sometimes we’ll talk to customers interested in our product, and they say, oh it’s a compatibility score. We say no, that’s not what we’re doing. It’s the opposite. We think no matter how high the genetic risks between you and your partner, you should be aware of those and then you can do whatever you want to mitigate those risks. This idea of being able to do embryo testing is a unique opportunity. Unfortunately, there have been couples that I’ve chatted with who are choosing not to have children because they’re so worried about their child being affected by a disease like schizophrenia or Type 1 diabetes that changed their own life. They’re choosing to adopt instead. It’s freeing and it’s an expanding reproductive choice to be able to say to those couples, “hey, you can have more control and confidence going into the process of having a child. And you have this ability to do IVF and to identify the embryo that’s at lowest risk for this disease so that your child has the highest chance of living a healthy life.”
That’s something that hasn’t been possible. It hasn’t been possible to build models that stratify risk for these complex diseases. It hasn’t been possible for single cell sequencing to get a high enough fidelity sequence off of a small sample. A day five embryo only has a hundred cells and we’re taking a five cell sample off it. It hasn’t been feasible because that’s a small quantity of DNA to be able to get an accurate enough picture off of that sample to be able to return these reports to parents. I feel grateful to be able to introduce something that hopefully will have a positive impact on these parents and their future children’s lives.
ALG: You said the company’s been going for about a year. What has that process been like? You’ve done a lot to get to this point. And you created the company after COVID started?
NS: Right before COVID actually. That’s funny that you mentioned that because I was talking to Balaji in January, which is when we had closed the seed round and I was giving him the rundown of what the plans were for the year. He kept interrupting and talking about COVID and saying “hey Noor, I know you want to talk about this. But what you should be thinking about is what is your COVID strategy.” And I was like, “it’s going on in China and it’s not necessarily going to affect us.” He was 100 percent right.
ALG: Oh, yeah. He was the bellweather in early January. He was the first person I knew being vocal about it.
NS: He was totally right. We should have cared a lot more about COVID then. But most of the time has been spent on getting these studies and reports built out. There’s a number of academic collaborations that we’re pursuing to publish the papers that are going to be coming out soon on exactly how effective this technology is, what’s the analytical and clinical utility. A lot of time has been spent on that. And the brass tacks of building the reports and getting pipelines set up.
ALG: On that question, it’s become more apparent that many COVID deaths and hospitalizations could have been prevented if we’d better understood the co-morbidities and predispositions to the disease and worked on mitigation ahead of time and had those high risk folks at home immediately. How do you think Orchid could contribute to our understanding and prevention of severe reactions during future pandemics?
NS: It’s powerful to understand your genetic susceptibility to disease. Fundamentally there’s only so much you can do in terms of changes you make to your health. You’re flying blind if you don’t know, am I predisposed to this disease and what are my starting conditions? One of the situations that I find frustrating is these diagnostic odysseys that people have to go on in the current healthcare system, where they don’t find out that they have something like Type 1 diabetes until their 30s. There’s something they’ve been living with their entire life. They’re extremely fatigued, they’re misdiagnosed and given the wrong workup over and over again. If you know what your risks are early, you can proactively manage them. You can get a continuous glucose monitor. You can get an Apple Watch. You can monitor your biometrics. There’s so much more you can do if you are able to have that information yourself rather than relying on a third party to direct you to the right place.
ALG: A question we have all faced as investors and builders is building remote. I’m an investor in a company called Synthego, a CRISPR company, they have physical labs. Bio companies like that need to be in a physical location, while companies like Coinbase are going completely remote. Where do you fall in that spectrum and how has it affected you the last year, building a team and getting going?
NS: I was anti-remote before it was forced upon us. But then I was shocked by how much we could get done remotely. We’ve spent a lot of time on software and shifted to the wet lab work once COVID died down a bit. I’m excited to get back in person, as soon as the team is double vaccinated. What about you, did you feel like you changed your impression?
ALG: It feels dependent on every company and team. If the team knows each other from before, that helps. You’ve got those bonds if you’ve already met each other and worked together in person, then it’s easier to go remote. We’ve gotten used to doing deals without meeting founders in person. I think business development has worked the same way. But for starting teams, I don’t know. I think we’ll all evolve to being more digital, and meeting face to face just occasionally because you get a lot of information in one meeting. I know that I personally don’t need to be seeing my team every day face to face to get things done. It can be distracting. But it’s impressive that you’ve done this in a challenging time and especially with wet labs, which are overloaded right.
NS: Yeah. Someone you should talk to is Fred from Curative. He went from completely startup lab at the beginning of the pandemic to processing 10% of COVID tests that were being run by Curative. He had a crazy year — last year he went from two or three employees to over five thousand in less than a year in order to meet the COVID testing demands. Lab testing has been insane over the last year because of COVID.
ALG: I did see that Barry Behr recently joined you as an advisor. He’s famous for his work with embryos and is director of Stanford’s IVF lab. Tell me about the team you’re assembling.
NS: Since we were born out of Stanford, a lot of the folks that are involved are all from the West Coast.
ALG: Stanford mafia.
NS: Ha yes basically Stanford Mafia. It’s funny, despite the fact that we’re in a totally digital world right now, it’s been based on proximity, who we spent a bunch of time with in person before COVID. It makes it more insular. I’m excited to go out and talk to people from not just within a 30 mile radius of Stanford University.
ALG: I’d like to get into your background. You grew up in Virginia. What shaped you as a kid? Do you think there are things you can identify back then that have translated into Noor today and how you’re wired?
NS: One of the biggest things is something my dad always laughs about, which is that he thought an important value to instill in his kids was to question authority and to develop your own opinions and not regurgitate the opinions of other people. Whether that’s a news source or a book or anyone else. In my siblings that value was instilled into them. But he said that for me, it went into overdrive. He’s like, “I wish you actually became a little bit less contrarian” —
ALG: You were. on the edge of being a rebel without a cause, or causing trouble at the dinner table?
NS: Exactly. Growing up, there was a huge number of debates I used to have with my family. My dad said, “you don’t even believe in this point. You want to represent the contrarian and see how far you can get with it.” That’s something that has stayed with me. I became comfortable with doing something despite the fact that someone else might find it bizarre to do that. When I went to do the Thiel Fellowship, everyone said, “this is the absolute craziest decision. Why would you do this? It doesn’t make any sense.” Then after the Thiel Fellowship I went to Stanford and I got the exact same response, “why would you go to college after the fellowship? That doesn’t make any sense?” I’ve always been comfortable doing things on my own terms. If it makes sense to me, I’m going to do it despite what other people think makes sense.
ALG: The quality of the people that go through the Thiel Fellowship is amazing. There seems to be that common thread of independent thinking, which I’m sure they select for. So I guess I have to ask you Peter’s question — what contrarian belief do you hold?
NS: I think it’s “what do you believe to be true that very few people agree with you on.” The one that’s most related to Orchid, is that it’s going to become as common as vaccination to measure and quantify your genetic risks. It seems crazy that right now people are going into the most consequential decision of their entire life blind. They do more research on Yelp trying to find out what the best place to have lunch is than they do when they’re rolling the dice on the health of their child. So that’s contrarian right now, but won’t be contrarian soon. It’s probably a five or ten year window. When Counsyl came out, expanded carrier screening was considered too much testing to be done before pregnancy. Then just a few years later it became mainstream.
Similarly that happened with NIPT — noninvasive prenatal testing — at about ten weeks, you can discover what the chromosome status is of a 10 week old fetus. You can discover whether or not that child has Down syndrome. Then you can make the choice of do we want to continue this pregnancy or do we want to terminate it based on the results of those tests. That was controversial in 2012 when it was introduced. Just a few years later, it became one of the fastest adopted diagnostic tests in medicine. And it’s standard now in the U.S.
The more funny examples are the ones further in the past because they’re not as heated anymore. Things like birth control. It was first introduced as something that would mitigate period pain and then on the back of the box it said there might be a side effect of disrupting the potential to conceive a child. People were buying it for that reason — that off label side effect was the reason people were buying it. When IVF was introduced, it was thought that scientists were playing God and these were test tube babies —
ALG: Yes I remember someone went into the IVF scientist’s lab and smashed the test tubes. It was heated.
NS: It’s super interesting. I’m not sure why when it comes to reproduction everything is charged. Any endeavor to expand reproductive choice for women is always met with heat. Slowly that heat dissipates and it becomes standard. Even being pro-choice in the U.S. is still a heated topic, despite the fact that this is fundamentally a woman’s body and it’s her right to choose what she wants to do. My stance is we should continue to expand reproductive choice. We should give couples and parents as many options as possible, whether they choose to conceive via IVF, with the help of a surrogate, with expanded genetic testing, whatever it is that they want, that they can make an independent and personal decision. We should provide people with that data and those resources.
ALG: You might enjoy this book I was reading on the question of why people react so much more on biology issues. It’s called Daedalus or Science and the Future — it’s the text of a lecture that was read in 1923 by JB Haldane to the heretics society at Cambridge. It’s a short text because it was a lecture and he makes predictions about the future, from things like agricultural society to biology. He points out that across bio, chemistry and physics — physics today being, electrons and software and anything to do with I.T.— across those three, the reaction to technology related to biology is by far the most sensitive. I hadn’t broken it down like that for myself. Yes, some software is controversial, but far more controversial is biology progress. I recommend the book. It’s got contrarian views for 1923.
NS: What’s your answer to the contrarian question?
ALG: I’ve always believed that the Web is a legacy platform that is holding back innovation. It was good for a few years, browsers and whatnot were great. But when something gets good enough, people stop innovating. That lack of creativity around Internet innovation has been a shame, it’s been halted for decades. Possibly we are at a moment that it will start to accelerate and people will do more interesting and innovative things again — I spend a lot of time in 3D worlds and metaverses. I have a few other contrarian beliefs, maybe I’ll tell you offline.
So what do the next six months look like for Orchid? What should we be expecting from you and the team?
NS: We’re excited to release the embryo testing. It’s cool that we’re going to be able to return results to these couples via the saliva-based screening to understand what are their own genetic risks and what are the projected risks of their future child. It’ll be cool to be able to return this high resolution data, not just to parents and in a projection fashion, but in a real clinical setting in the IVF clinic. We’re excited to give those couples and their clinical teams access to the same data on their embryos.
ALG: I hope we’ll live in a world where we see a lot more of that and less disease. Thrilled to see you’re doing this, rooting for you and can’t wait to see what happens next.
NS: Thanks for having me.
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