Roche whole genome sequencing in 4 hours!

Thanks for watching episode #127 of the Doctor Podcast Show, and I'm your host, Doctor Robert Sicard. Please subscribe and follow Doctor podcasts and like and repost this episode. We'd really appreciate that and it'll help me create more excellent programs like we have today. Today's show is on a very important and fascinating topic that I think will have a huge impact on the practice of medicine in the future. It's about same day whole genome sequencing of human DNA, which is incredible. We have 3 great guests and experts on this topic today To explain it all to us, 1st guest is Mark Kochoris.

He's the Head of SBX Technology at Roche Diagnostics. And by the way, Roche Diagnostics is a division of the parent company Roche, which was founded over 125 years ago and has grown into the world's fourth largest pharmaceutical company by revenue. It's also one of the largest biotech and diagnostics companies and a global supplier of transformative, innovative solutions across major disease areas. Roche focuses on preventing and curing diseases with the highest societal burden with the goal of improving health outcomes and reducing costs for patients in healthcare symptoms now.

Mark Cocoris has nearly 30 years of experience working on the cutting edge of biotechnology, conceiving and developing innovative and transformative technologies. His vision of creating A next generation DNA sequencing technology that would enable broader use in health healthcare led him to Co invent the SBX technology in 2007. That same year he Co founded Stratos Genomics where he became CEO and in 2020 he led his company through the acquisition by Roche where the SBX chemistry could be further developed.

Mark, who heads all SBX research at Roche is an inventor and has over 20 US patents. Our other guest is Doctor Niall Lennon. Doctor Lennon is the Chair of the Board and Chief Scientific Officer of Broad Clinical Labs, the Broad Institute's wholly owned subsidiary that develops, implements and validates innovative technologies that enable transformative advances in scientific discovery, clinical research and diagnostic medicine. He has been with the Broad Institute for over 20 years and has contributed to the development of applications for every major next generation sequencing platform across a range of fields.

Dr. Lennon built Broad Clinical Labs to facilitate return of results to patients and to support clinical trials. Incredibly important. Our other guest is Doctor Monica Wojick. Dr. Wojick is a neonatologist and clinical geneticist at Boston Children's Hospitals, which is one of the top Children's Hospital in the USA. She's an assistant professor in Pediatrics at Harvard Medical School. She specializes in rare diseases affecting the fetus and neonate. She has post pediatric residency fellowship specialty training in both neonatology and genetics, and subsequently obtained her Master of Public Health degree to augment her clinical effectiveness and health services research.

She currently serves as the director of the Neonatal Genomics Program at Boston Children's Hospital and is the medical director of the Manton Center for Orphan Disease Research. Doctor Wojcick research focuses on the application of genomic medicine in the perinatal setting, particularly relating to genetic diagnosis. So I want to thank all three of you for taking time from your busy days and schedule to join us today to discuss one day whole genome sequencing, which is a really, really incredible.

Monica, I want to start with you. You were the lead author and important recently published article in the prestigious New England Journal of Medicine about same day genomic sequencing in newborn infants. Now you see these tiny patients in the NICU, which is the neonatal intensive care unit, every day. Can you tell us about one baby whose life was changed because doctors finally figured out the genetic cause of the baby's medical problems, even if it took weeks to do that genetics testing and evaluation in the past?

That's such a great, wonderful and timely question actually, because the the degree of impact depends actually on the timing of result. You know, you imagine if the results taking weeks, the life's already changed by the time the results are back, you know, so there are certain highly invasive procedures, you know, like organ transplants that can be life saving. But we wouldn't want to proceed with that unless it was clearly indicated because of the potential, you know, obvious risks. So one example I can think of is, you know, rare genetic pulmonary respiratory disorders where our babies are born with such severe lung disease that they're dependent on a ventilator and sometimes need to live on, on ECMO, you know, on, on bypass.

And it's really hard to, for the body to live that way. And the only way to get off of that would be a lung transplant. So anything you can do to prove they have, you know, a genetic lung disease and not some other non genetic condition that could spontaneously improve over time that can shorten the time to transplant and improve their outcomes. So in the past, we've had babies that didn't get a transplant that they needed until they were several months, even close to a year old and, and, and sadly others that haven't survived to that point.

But recently, you know, we've been able to take that diagnosis in two to three days and shorten that window before transplant to weeks to months. And you know, that's such a tremendous benefit that we feel very lucky to be able to provide now. So by getting the genetic testing, you're sure that this is a genetic disease and not some other issue that'll get better on its own? Exactly. That's right. Wow, that's that's amazing. So Mark, congratulations on being co-author in the New England Journal Medicine article.

Many people think that DNA is just a twisty ladder. What we remember from kind of high school biology in recent years though, people now understand that DNA is billions of molecules arranged in a specific sequence and configuration, and it codes for our genes and our chromosomes. Can you tell us what a genome is and what genome sequencing is? Yeah, that's great. Thanks, Robert, and thanks for having us today. It's just, this is great. Yeah, fun conversation. So, yeah, a genome is essentially the complete set of DNA from an Organism.

So it contains the instructions for development and function. It's essentially like a a master operating manual, if you, if you want to think of it that way. So when you read someone's genome, you're determining the precise order or sequence of the DNA code, which is composed of four molecular building blocks called nucleotides, which are often referred to as in shorthand as ACG and T That's usually how everyone refers to the chemistry there, ACG and T. So to sequence a person's genome, you'd isolate a sample there of DNA, either blood, tissue, swab, other means of of isolating DNA, and then use the technology like the one we'll talk to here, SBX to actually sequence their genome.

And this information is is Monica and Nile know well know is is useful for understanding predisposition disease or helping manage complex diseases. Right now, you mentioned ACGT as as the molecules. How many billions of those molecules are there that make up our entire DNA? Well, the the human genome is about 3.3 billion bases or nucleotides together, strung together as 11 big information storage system, as I like to call it, yeah. Almost like computer code. Now, what does it actually mean to read someone's genome?

Mark what? What does that mean? What do you do when you're reading someone's genome? So actually that's the process of, of sequencing and, and measuring the, the sequential order of these molecules. So you know, the, the, the first draft of the human genome was, was actually published in, in 2003. It took thirteen years in the cost of $3 billion to generate first reference genome. So we've come a long ways in our ability to to sequence a, a person's genome. And so, and now the pace of this technology innovation has been tremendous.

I think it's outpaced Moore's law in terms of the integrated circuit doubling time sequencing I think has actually outpaced that. So, and this led to dramatically improving efficiencies, driving down costs and reducing time necessary to sequence. So the Roche technology we use here, it's called sequencing by expansion or SPX and we can talk about that later if we'd like, brings new capabilities that allow for even faster, more efficient sequencing. So the work we did here, we sequenced the human genome in less than 4 hours, which to use the scientific term is, is bonkers, right.

I think that's, that's what we can agree is probably a good, yeah, a good term. So. And you know, how much, Yeah, faster could we do this? I mean, that's, that's open question. You know, the actual sequencing time time only took about 15 minutes. It was the other steps before and after that that add up to the four hours. So but I also want to say one thing well, well, Niall and and Monica are here is what great teams this was for this project and what fun this was. So my, my team in Seattle did an amazing job of compressing all these workflow steps necessary to do the fast sequencing.

Our computer science guys compressed all the algorithms for this. And of course, Broad and and Boston Children's like really top notch. A wonderful group of people to do an exciting project. And I think on one personal note, I have to say I had a nephew Ryan who was born with chromosomal deletion and it was 20 years over 20 years ago. And just seeing how the uncertainty, all the biopsies and endoscopies, all the things they had to do 'cause they just didn't know what was going on with Ryan and, and having the the idea that into the future we're going to be able to do these kind of things more and more often is it's just awesome to be a part of.

And so I want to thank Monica for what she does and Niall for what they do as well. So let me summarize that. What used to take 13 years now takes it's 4 hours. It's but that but that's really incredible. Now, Niall, congratulations also on being the co-author of the New England Journal medicine article. Now you run one of the world's biggest DNA sequencing labs at the Broad Institute. How long did it take to sequence a few full human genome when you first started doing this? And and what did it cost back then to to do that?

Yeah, thanks. Thanks, Robert. As as Mark mentioned, the the very first human genome, you know, was actually sort of the technology didn't even exist to do it in a single lab when that when this project started and it needed to be an international consortium to do it. And that completed about 2003. I joined abroad, I mean in 2005, just a few years after that first draft was published. And that was really the beginning of what we would sort of say is the genomics revolution, the initial human genome project really, you know, like a, a space race sort of kicked off this wave of technological and computational development that led to newer technologies being developed and that allowed us to actually start to do human genomes in single labs and ultimately, you know, in single days.

So when I first started, it really still wasn't possible to do a sort of a human genome in any kind of, you know, cost reasonable way. A few years on, you know, in the in sort of the 2006, 2007 time frame, we started to see new technologies be developed that allowed us to start to think about doing human genomes more frequently. But it was still even a few years after that into the 2000 and 10s when the cost came down to be 10s of thousands of dollars at that time, that we started to, to, to do more human genomes more routinely.

And it would still take us many weeks to do them. And Fast forward into, you know, the last few years. Now we do sequence human genomes somewhat routinely. In fact, in my lab this year, we'll probably do about 170,000 human genomes to serve the research community and the clinical translational community that we work for. And those genomes today cost a couple of $100. And, and typically if we're not rushing them again, they'll take several weeks more. Not that the sequencing time itself takes several weeks, but that the, you know, process of getting the samples in and and pushing them through takes several weeks.

So we went from many, many years to now in routinely in sort of the research setting being several weeks and being a couple of $100. You'd say it's probably typically under $500 today to sequence of human genome just from the, you know, the data generation part of the process. Wow, that's incredible. Now, Monica, you, you touched on this briefly before. In the past, parents might wait two to six weeks or longer for genetic results so that you can figure out what to do for their baby. What does that weight feel like in the NICU for for doctors, for you, and for the anxious moms and dads of the baby.

Yeah, it's such a great question. And, you know, families come to our NICU under all different circumstances. And some know, you know, from prenatal testing that their baby will have medical problems. But but, you know, if we think about the families that were entirely unsuspecting, so they thought they had a healthy pregnancy, a healthy baby, and now they're here in the NICU and their baby has persistent seizures or they can't breathe, they're on a ventilator or they need emergency surgery. You know, I think for many families, this is the scariest, absolute worst moment in their lives as parents.

You know, and they're hearing from doctors this wide range of possibilities. You know, there could be healthy life. There could be potentially death. And the, you know, parents and doctors are trying to make these important decisions really in this void. So, you know, you can imagine there are families that are just hanging on waiting for this result while their baby is on life support. And that's, you know, an uncomfortable feeling, to say the least, for doctors and patients alike. And for me, those are the ones where I'm calling the lab, emailing everyday to say, you know, can you tell me anything yet?

You know, we're just waiting for this to go to make the next move. So, you know, it's, it's, it's a challenging situation to be in for parents. I can't even imagine what they go through. Right. So this has made things much better for you and and for families as well that that's really great. Now in your study that I read, there was one baby who got a a same day answer that explained their seizure disorders. If that result had come back in six hours or four to six hours instead of days, how might the treatment have changed for that baby?

Yeah. I mean, I think even though our current rapid genetic diagnostic diagnostic approaches are very good, you know, as a as a neonatologist, they also want to acknowledge that our clinical diagnostic skills are pretty decent as well. So when days are coming, when the results are coming back from the genetic tests in days to weeks, often we already sort of know what we're dealing with and have initiated appropriate treatment even by their time the results are back, which is what happened in in this case.

And and remember this is a research study, so we were trying to time these results for a period when we'd have the clinical result returning around the same time as the same day result. So this is all somewhat hypothetical, but you know, given that there are certain genetic epilepsy syndromes that have particular treatments that are the most effective, you know, if we had the results the day that the baby started seizing, we could use the most effective drug, you know, as that first line therapy instead of starting down our usual pathway that involves trialing different agents to find one that works.

So it could really shorten that, you know, therapeutic the time to effective therapy as well. Right. So this is customized personalized medicine at its peak basically that. Absolutely, yeah. That's incredible. Now just theoretically if if you can do a a whole genome analysis in a few hours, could you in the future possibly theoretically use something like CRISPR or other DNA editing to actually fix the genes? You know, I think in terms of the gene therapies and CRISPR etcetera, it's we have a very exciting future ahead of us and, and not everything can be completely reversed.

But I do think that, you know, what important aspect of these gene targeted therapies is that you really need the precise genetic diagnosis to access them. So I think our job and the power of this collaboration, you know, especially was to make these diagnosis as fast as possible so that our patients are eligible. And, you know, and that's, I think the the incredible potential that we have here. Right. So Mark, now Roche just published this breakthrough in the article that we've been talking about.

Let's dive a little deeper into this amazing Roche technology, Roche. And you invented something called sequencing by expansion, which you mentioned earlier, or SPX. Can you explain what that is for the average person in the audience who has great interest in the latest medical technology and advances, but not that much expertise or knowledge? Basically, how does SBX work? Tell us a little bit about the XNTP molecules and the nanopores, and how do you go about translating a sample like blood into DNA information in four hours?

Yeah, no, that's great. Not this one I can talk about for hours. And I, I think I actually have sometimes I kind of can go on and on. So I'll try not to go too much into the chemistry here and try and, and cover it and, and maybe use a couple examples. So I mean, basically our approach to efficiently sequencing DNA is to not sequence DNA. And it's kind of a weird statement, but you know, we, you know, and it'll be clear later on. SO4 nucleotide bases I referred to before ACG and T make up DNA, they're spatially compact information storage system as I as I called them before.

And the bases are actually structurally quite similar. So this basically means this is actually a really hard measurement challenge. If you have all these bases, you have to do this resolution. How do you do that efficiently? These are sub nanometer spatial resolution. So this from a measurement standpoint is extremely difficult and every sequencing technology has to resolve this figure out how to solve this problem. So if you think about, you know, small font in words that are spaced really close together and you can't see them.

Now imagine a bigger font with better spacing. Like on my wife's cell phone, for example. She's going to kill me, by the way, biggest font I've never seen in my life. But it's, it's a, it's a great example because, you know, you can actually resolve the large font. And so, yeah. And it's similar with SPX. So we essentially increased the spacing or expanded the, the, the, the, the structure so we can measure and, and detect these more easily. So to do this, we created a biochemical conversion process.

And so this used enzymes and chemistries that never existed before. And this, and you'd mentioned the XNTP, this expandable nucleotides. So it's not a regular nucleotide, it's an expandable 1. And we use that to create the surrogate molecule called an expandimer, that's a surrogate of the original DNA. So now it's no longer DNA. It's this new molecule that's highly engineered, that's about 50 times expanded relative to regular DNA. And the idea is, is that, and you know, I got a picture behind me.

So the idea is, is that now you can measure this molecule a lot more efficiently at higher speeds. And so now you see it all kind of coming together here. And so the way we did that was we brought another technology together called a nanopore sensor array. So the idea is as you use these small protein pores where you actually thread the DNA through the pores and you can measure electrical signal changes of this long expandable molecule and do that really, really efficiently. So this is like radical technology that to be able to do this at the speed and throughputs that we we do here and so on, all of that works hand in hand with accelerated compute and and, and and analytical methods of how you actually take that data streaming off very efficiently.

So all of it kind of comes together. So with SBX, we essentially rescaled the structure of the molecule to solve the problem. So it brought on tremendous chemistry challenges, biochemistry, these things were never done before molecular engineering. And also we had to break a lot of rules to make this work. But I'm really glad we did because when you see, once we finally figure out how to do it and it was 2007, we started the company, it actually has a pretty amazing outcome. Wow, that's incredible.

I love that analogy of increasing the font so you have more spaces. It really explains it well. Now. My understanding is that you began working this in your startup company before Roche bought your idea. What was the aha moment that made you think same day sequencing was possible? When did you realize that you were on the brink of this incredible discovery that's going to change the world eventually? Yeah, that's a great question. A little bit about the startup company. So I Co founded Strauss in in 2007 with my friends Al Stefan and Bob Mcgurr and they actually had an engineering consultancy.

Al was the CEO of of this engineering consultancy and it's called Stratos Product Development. So you see where the name came from. Bob was the CTO and so I brought the idea to them. We, we knew each other through work and collaboration. And so at some point we brought this kind of backy idea about, you know, changing the DNA molecule. And it was just, you know, this is one of the things that that, you know, history, the three of us coming together. I think we all wanted to do something that was game changing and we saw it in this because we saw about how it solved the measurement challenge there.

And so, you know, the way we looked at it, honestly, the fast, the speed, the flexibility, these are all rooted founding principles of SBX. So it really wasn't an aha moment for us. Really it's more about, you know, the evolution of the technology to get to this point. But I'd say probably about two years after the acquisition where where SBX came into Roche, when I was seeing the throughput, seeing the capabilities coming together, I thought, OK, we're probably going to be able to do this. And that was, that's pretty cool.

Wow, that's amazing. Now Niall there there are commercial labs that offer fast DNA tests in in days but not hours. Why wasn't that fast enough? And what convinced you to team up with Roche on this amazing new 4 hour version? Yeah. So as I mentioned earlier, you know, most of the genomes that we do, the 10S or hundreds of thousands of genomes that we sequence per year are really in service of discovery or, or research, you know, research into certain diseases, disease foundations, federal awards and, and pharmaceutical companies.

And for the most part that those studies really are looking at data in aggregate. They're looking at large cohorts of, of patients or, or disease individuals. And so they're, they don't really need their genome to be done in hours. So, so that's how sort of most of our genomes are done. But over the last several years, there has been a growing appreciation that rapid genome sequencing could be useful in certain contexts, one of which is the NICU. And this was advocated for by many groups, but most notably, I would say, in our community.

Doctor Stephen Kingsmore at Rady Children's Hospital in in San Diego has really been a trailblazer in this area. It was Stephen, in fact, who set the first world record for doing whole genome sequencing in the NICU setting. Subsequently, Dr. Ewan Ashley at Stanford had, using a different technology, set a newer record for how quickly you could do the DNA to variance from a human genome. And that was the record that we actually beat in this project. So however, in despite those sort of demonstrations, which were really, you know, Seminole in, in sort of showing what could be possible, the difference was that the way they were done wasn't really reproducible in the everyday setting.

It was done in sort of a heroic way to show what was possible, but the technologies and, and the process and the cost associated with doing it that quickly weren't really feasible to do in a, in a, in an everyday setting. And so as we were working with Roche on this new SPX technology that Mark invented, as we started testing it in the lab and realizing that it could be done at at this speed, not as sort of a one off heroic effort, but actually that was just the way you could run it. And with certain tweaks that Mark's team did, we could do it even faster in, in our group, we were coming into that with the context of knowing the work that had come before.

And we said, gosh, actually, we think we could show that this could be done routinely at this time at this kind of speed. And if you could do it routinely, that might actually make a difference to people like Monica who need to who need to see this data routinely. So it was really where the the collaboration came together where we had been working with Roche on the technology evaluation and then reached out to our colleagues at Boston Children's and said, look, what if we were to demonstrate that we could do this not just once, but actually over and over and over again over a period of time to show what's possible once this technology is more widely available to bring down the time and get you the results on the same day.

And as Monica has described in their setting today, they've modified or at least they think about their clinical workflow with the assumption that the genetics data will come back in this sort of five to seven day period. And so you kind of work around that assumption, but actually demonstrating that we could do it on the same day completely breaks that assumption. And going forward, if we actually make this routinely available, then I assume and Monica can can sort of say, I assume that the actual thinking about how to use this information will change as they think about these cases going forward.

And so that was really the context of how you know which, which is essentially our day jobs at at Bro Clinical Labs is how do we work with really exciting novel technologies and then bring them to the clinical genomics world so that they can make a difference. Right. So it's, it's a team effort, it's it's Roche and you and your labs and the doctors and ultimately the patient's benefit. Now, Monica, this is currently still a research. Tool. But if it becomes a regular everyday clinical tool in the future, and possibly every NICU eventually has this available, what's the first thing you'd want to tell parents on on day one about this?

Well, I, you know, I think the message in some ways is really still the same that, you know, our job as doctors is to find out everything we can do everything we can to figure out what is happening to their baby, to find the explanation. And you know, we're there for them every step of the way. I think we think about the, the immense importance of same day results and how they can influence these really critical care decisions. But you know, I think for the, the parents journey, you know, in some ways, it really starts on that day that you received the diagnosis and then you have to figure out what to do beyond that.

So, so that level of support and kind of just working through it is going to be so critical. And perhaps even more so if we're actually coming in with a diagnosis on the same day that, you know, or maybe the day after we even bring up the idea of a genetic condition. So this is a lot of information for families to to process. And I do think that that message that we're, we're there as, as clinicians to really help them work through it is, is not to be lost in this process. That's great. Now, Mark, regarding Roche's role, you didn't speed up DNA reading here.

You also focus on quality and thinking about lab scenarios. Why is that important? Why does that matter? Yeah. I mean for the fast sequencing that we did here, we had to reduce, as I mentioned before, all the the workflow steps in order to get to this result and at the same time maintain quality. I was really happy to see the quality of the sequence. We won't go into technical details here, but it was actually quite, quite good the quality we got out of this sequence. So that was I think really an important part of this that we hit that standard.

But a couple thoughts on lab scenarios. So SBX will launch as a research use product and we'll call it the Excelios platform is what it's called. That'll happen next year and I'm really excited. I think this is something I've been thinking a lot for many years about. I'm really excited to see what researchers do with these capabilities and how they bring this this capability of SBX to bear. So of course faster results for time sensitive applications is this is great. But then also thinking about ways to implement SBX scale, whether it's a 24/7 operation or running more flexibly for low volume users in in labs that don't have that kind of throughput.

That's one of the strengths of being able to flexibly, you know, lab scenarios where you're flexibly running and doing sequencing and then really rethinking in these in this format with SBX how to improve operational efficiency. So those are a lot of the things that think about or, you know, on the other side, testing new applications, like there's things we haven't thought of. And, and when you have a new tool you can think about, you know, other ways you can sequence that, you know, either you hadn't thought of before or you really needed something, a new technology to enable.

And but then one last thing on the, on the lab scenarios, I believe there's a cadence and momentum to science and innovation. And I'm inherently impatient, as my team knows I want to get results fast and always. But I do believe there's a momentum to innovation and and information coming back to you. That having that flexibility and ability to sequence faster and get information in a timely way can maintain at a research level momentum because it's not inevitable that innovation and ideas will come to you.

I mean, I can think about all of innovations we've made. You had to be ready for them when they came. And and I think there is that timeliness that I'm really excited to see how people leverage once the technology gets out there. Right now, Niall, you, you tested this on real NICU babies, not just lab samples. What was the most surprising thing that worked or that didn't work when you tried it in the real world? Yeah, I think, I mean, I think one of the most surprising things was it actually worked so well.

You know, we are, we are fairly used in our group to trying new technologies. And, and as you said, often times the, the things we try on them first are really control samples or reference samples, samples that, you know, really high quality DNA where we know the answer and, and those samples can work well. However, the big leap for many new technologies is actually being able to use them on real world samples. And real world samples aren't as neat and clean as these laboratory samples. You know, when you when you get blood from a baby and when you get different types of specimens, you know, things can happen.

The, the DNA might not be as high a quality or there might be things in the blood that are not in your control sample that throw off the technology. And actually we didn't see any of that. And so really going from the, the control samples to the real world samples, you know, the, the quality of the data, the utility of the data was no different. And that was in itself really, really surprising. And, and I think the other part with any new technology with, with all respect to Mark as well, we ought, we are used to new technologies coming in and then like it works great one day and then the next day it breaks.

And that's just, you know, we're, we're OK with that. We, we got early access to these technologies to help companies kick the tires and find out how they might not work. But again, here in the study, we over the course of three weeks, we were doing samples, you know, every day, every other day. And we didn't have those sort of technical issues. You know, it worked when it needed to work, which for a technology sort of pre commercial like this, that itself is sort of surprising and, and, and great to see and very encouraging.

Wow. So Mark, when when are you getting your Nobel Prize for this? It's funny actually. Two of my old colleagues from my first company won the Nobel Prize last month. So. Oh, really? Oh yeah. We had a nice, we had a nice party for them, so yeah. That's awesome. So Mark, now Roche spent years and I assume millions and millions of dollars turning your idea into a reality. What part of this technology is uniquely Roche? And that's something that no one else could do but Roche. I mean, well, first the most important part was Roche brought two companies together and they brought Stratosgenomics together with the SPX chemistry and then Genie.

Genie was a company that had the sensor array technology I referred to before. But it's really not surprising that we ended up at Roche. I mean, PCR, they brought PCR to the world. And PCR was kind of my inspiration as a young scientist. I looked at that and I, I was just blown away the first time I did PCR to amplify DNA and I, I just thought, OK, this is, this is amazing. So I'd always had that in mind that Roche would be a great suitor for this technology. And they've certainly brought uniquely facilitated this coming together of these two.

And I call them historic technologies because they really amazing chemistries and amazing, you know what Genia did in terms of how they solve the the sensor modules challenges. But then coming together, Roche did a fantastic job of bringing those together. They have a long game look when they bring technologies together, they have a Longview of that and then certainly have the global capabilities to broadly bring SBX to the market. So I think all of those things were in mind. Right now, Mark when when you walk into a research lab in in 2026, next year, what does the Roche SPX machine look like?

How big is it and can you describe it for us? Yeah. I mean, well, I hope it's well used. Looks well used. That's what I'm. Yeah. And I expect there'll be a lot of enthusiasm around using this new technology, learning, I think, new workflows. Again, there's some amount of learning how to sequence differently because it is a very different approach. And this is a good thing. And as far as how it looks, it's essentially 2 tabletop systems, 1 is the sequencer and one is the actual unit that does that SPX chemistry, that conversion step that I talked about before.

And so and you can see if you go to Roche sequencing, you can see a website that we have and you can see all kinds of information on there that talks about, shows images of what the instruments look like and has a lot of background of the technology. That's great. I'll, I'll include that in the podcast Now, Monica, doctors usually aren't that comfortable trusting black boxes when they're taking care of very sick patients. How did Roche prove to you that their 4 hour DNA result is just as accurate as what used to take 5 or 7 days in the past?

Yeah. Well, I should say that, you know, the opportunity came to me via the Broad Clinical Labs team. And I was already familiar with several of their team members and their work from my own work with the Heidi Reim at the Broad Institute. And so I've always thought very highly of of Niall and his team. So when I think it was Sean Hofer and Katie Larkin from Broad Clinical Labs told me that, that they thought the genomic data come off, coming off this new Roche machine was high quality. That was honestly pretty good is good enough for me.

But we did send them 5 cases that we knew from Boston Children's from the Manton Center that we knew had diagnosis to, to make sure they could find them. And then they did. So that also helped. And then finally, you know, in our study, we, we ran clinical testing through our usual clinical lab in parallel. And those results also matched what the, the bird team had found. So none of that was surprising to me, but because you know, this is I think it was a collaboration that I was very much looking forward to with, with the team that I really I value and trust.

So I didn't really have many doubts, I can say. Wow, that's amazing. So you must have been like amazed with the results when they were identical to the older technology, right? Right, but so much faster. Wow. Yeah, huge difference. So Niall Broad Institute is a nonprofit Research Institute, and Roche is a giant international, highly respected pharmaceutical company, diagnostic and medical device company. How does that partnership actually work, the two of you working together? So at the Broad, we've been in the business and at the forefront of evaluating new technologies for sequencing DNA, you know, for as long as I've been there, for the last 20 years since these technologies first were invented.

And as I mentioned earlier, we are one of the largest sequencing labs in the in the world. And so we are really good at understanding what makes a good technology and a bad technology and also really thinking about there are many sequencing technologies and, and they're sort of fit for purpose for lots of different applications. You know, and we serve through our community, our academic community at the Broad Institute in our and at our affiliates at Harvard and MIT, we are used to generating data across a range of application areas from infectious disease, common disease, rare disease and cancers.

And so because of that, because we have a really active user community, we're making great discoveries using this data. We are often one of the first groups that companies who have a new technology for sequencing DNA come to and ask us, you know, would you be interested in working together and helping us and thinking about the applications of our technology. We don't always say yes, but certainly when Roche approached us, we were very excited to say yes. As we heard more about the technology, we got even more excited.

And as we got our hands on it and started to see what it could really do, we got even more excited. And that's when we brought brought in Monica and the team at Boston Children's. So we're very excited that this partnership worked out. Yeah, great story. Now, Monica, currently again, this is a research tool, but do you see possibly a day in the future where every newborn baby gets a full genomic sequencing at birth so that pediatricians are alerted to potential medical problems that the baby will face as a child and adult?

Because it's, it's good to know this information as early as possible. Do you think that's a potential use in the future? Yeah, and I think so. And there, you know, there are some large studies looking at that that very issue. I, I do think, you know, one important distinction I want to make is between genetic diagnosis and screening. Because I think a lot of people here, you know, genome sequencing and they assume genomic screening, but that's really where you're looking at the genome of a baby or anyone who's healthy, asymptomatic, and you're trying to find diagnosis they weren't aware of that could cause future disease.

And, but I kind of want to contrast that to the studies like ours where we sequence babies that were already symptomatic to try to find out what's causing their symptoms. And I think the, the distinction's important because the way you go about looking for reporting variance is different and kind of the diagnosis, you know, versus screening realm. And for, you know, because our knowledge of genes and variants that cause diseases is incomplete. For screening purposes, you try to restrict what you're looking for, whereas for diagnostic purposes, we tend to cast, you know, much broader net.

And then also just the psychosocial implications of receiving a diagnosis for your baby who's already sick compared to one that is healthy at the time, you know, are quite different. But I do think that regardless, you know, more and more babies are going to be getting sequenced. And in fact we have a protocol at Boston Children's in our NICU right now to offer a rapid genomics universally for babies that come into our NICU for diagnostic purposes. And I, so I really hope this availability will spread, you know, especially for the babies that we care for, you know, in our NICU's that are, that are already sick.

Right. Do you know if this would potentially be covered by insurance in in the future? So that's a complicated question. It's definitely reasonable to say that that earlier, earlier diagnosis is better. I think given that the cost of the faster techniques tends to be higher than the slower ones. Again, all these are much better than they used to be. I think it it might be a hard sell at this point for insurance companies to pay for, you know, a same day test outside of an ICU setting as as Niall had alluded to earlier.

But but it's an interesting question to ask. You know who who needs the diagnosis same day, who can wait two or three weeks, You know, even in ICU. It might not be one-size-fits-all, but but I do think, you know, payers are coming around certainly to covering rapid genomic sequencing for critically I'll babies and children and and I hope this would similarly, you know, be included. Right now, Mark, again, it's a research tool, but could same day DNA sequencing be helpful for adults as well? For example, could it help you predict somebody who's predisposed to certain types of cancer, heart attacks, strokes, infectious diseases?

So is is there a role in the future possibly for doing this on adults as well? The same day genetic sequencing? Yeah. I mean, I, I think you can imagine a range of time sensitive applications that could emerge using SBXI. Think this was a great one, a great example of that. But I think certainly infectious disease is an interesting area, but I think there's quite a few that will merge that people like Monica and Niall and others will, will, will come up with. And so having that tool there, I think sometimes when you make a tool, people will be motivated to use it in in a certain way when it has that capability.

So, but I'd say our focus is the same as it has been at Roche is to continue develop capabilities, enhancing those capabilities and just thinking about speed and throughput, efficiency, cost efficiencies. Read link is 1. We didn't talk about reading longer fragments than the ones we currently do. All these type of things will continue to the future. And I like to say we're just getting started with SBX, even though, you know, it's been a while and I I joked, I said I had a long hair when we started.

That's not true actually, but it's been a while with the technology. But I think, you know, it's, it's kind of always keep innovating. I mean, Niall knows this from so many years at broad. You keep advancing, keep bringing capabilities. And I just really look forward to seeing what people come up with, you know, how to use SBX. Right now, Niall, again, it's a research tool, but do you have a a guess of when this might be something that's used routinely in the hospitals in the future? Yeah, I think it depends who you ask.

I know some of my colleagues at Boston Children's would would like that to be ASAP. You know, as Mark alluded to, I think Roche has said this, this technology will become commercially available next year. And so when it becomes commercially available, it will launch as a, as what we call an RUO or a research use only instrument. And that means that labs will be able to purchase it and use it for research purposes and that's what Roche will sell it for. However, in in the US clinical laboratory setting, we are as a clinical laboratory actually able to then purchase a instrument even in a research use only instrument.

And under the CLIA regulations, we as a laboratory can develop what's called a laboratory developed test, which means we validate the use of a set of instruments, reagents and assays for clinical use and on in our laboratory then we can offer that as a clinical test under the CLIA regulations. And so that's something that certainly we will be working towards once the instrument is commercially available. That's great. Now Mark, you seem to me to be able to see into the future a bit based on on what you've invented and and discovered.

Can you tell us what else you're working on with Roche, with SBX and other similar or different technologies? Yeah, I mean, I think there's never a never ending limit of of things you can do. And I think the thing I like about with SBX is it was such a impossible challenge. I think when we started on, you know, all the things that we had to prove what was, what was possible. And I think that's one of the messages I like to get out there is, is, is I, you know, I remember going around talking with people about, hey, this is this, this idea we have, we're going to take DNA, we're going to change it into something else.

And I think just, you know, that we were able to do that in that example of how to innovate. And it was really not easy. It was, you know, so many ways that we could have failed. So much innovation had to happen. I think it's something I think about a lot and I think about having gone through that, what other innovations we can do. So it's always there, you know, by me, for me. First, I want to get this to market, get this out in people's hands, keep advancing the technology. But yeah, there's, there's a lot of a lot of ideas and capabilities that come, you know, in terms of, of that kind of vision I think for the future for, you know, you know, empowering researchers to accelerate their discovery, really unlocking complexities of biology and then really democratizing sequencing.

So these are all things that I, I think a lot about both in terms of sequencing, but then other, other aspects of innovation that could be brought to bear knowing that, you know, you can actually do something like SBX. Yeah, it's incredible. So I want to congratulate all of you for this incredible accomplishment. It's going to make a huge difference for, for patients, there's no question about that. And I'm looking forward to it being available broadly around the country and the world. I, I want to thank you all for taking the time to educate us about this important subject so that the average person can understand the significance of this.

So thank you very much for your time and knowledge and expertise. We all appreciate it. Thank you, Rob. Yeah. Thanks. Thank you for having us. Yeah.

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