Researchers at Children’s Mercy have developed Astrolabe, software for predicting a patient’s response to medications using whole genome sequencing. When used with a newly developed, low cost sequencing method, the software can identify the pharmacogenetics profile of each patient, enabling physicians to tailor medication selection to the patient’s DNA.
Join Neil Miller, Director of Informatics and Software Development in the Children’s Mercy Genome Center, as he introduces us to the Astrolabe software and the benefits it will offer to physicians and our pediatric patients.
Selected Podcast
Translating Genome Sequences into Patient Prescriptions
Featured Speaker:
Neil Miller
Neil Miller leads bioinformatics analysis and software development activities for the Center for Pediatric Genomic Medicine at Children’s Mercy Kansas City. With a focus on applying high performance computing to clinical and research applications, he has designed and developed multiple software systems for the medical interpretation of genomic data. Mr. Miller holds a bachelor’s degree from Tufts University. His previous positions include Deputy Director of Software Engineering at the National Center for Genome Resources, Senior Software Engineer at iXL, inc and Applications Developer at Genome Therapeutics Corporation. Transcription:
Translating Genome Sequences into Patient Prescriptions
Dr. Michael Smith (Host): Alright, so our topic today is translating genome sequences into patient prescriptions. Neil Miller is my guest. He’s the director of informatics and software development at Children’s Mercy’s Genome Center. Neil, welcome to the show.
Neil Miller (Guest): Thank you, glad to be here.
Dr. Smith: I read in your bio here that Children’s Mercy sent over to me and I find it pretty fascinating what you do. I thought maybe we could start there, Neil. Just tell us a little bit about yourself, how you got interested in genome sequencing, and how that brought you to Children’s Mercy.
Neil: Sure, absolutely. My team is in charge of all of the bioinformatics analysis, high performing computing analysis, and software development in part of our Genome Sequencing Center. The backstory to all of that is just that DNA sequencing instruments produce an enormous amount of data, so you really need computational tools to make any kind of sense of it. I have now been at Mercy for five years – or almost six, now that I think about it. I was part of three folks who came from a small research institute in Santa Fe New Mexico, called the National Center for Genome Resources. We came to Children’s Mercy with the intent of establishing a genome sequencing center that would be integrated with patient care. We were trying to take a lot of things that we had done in a research context and really bring it to the front line in clinical care. I got my start in bioinformatics in the late 90’s, actually. I was introduced to the field as a software engineer and because of peculiarities in my skill set, I ended up out of the gate getting hired by a biotech company and that led to a position at the National Center for Genome Resources, where I was for ten years. It’s been a really interesting ride for me.
Dr. Smith: Right.
Neil: I got my start in genome sequencing, probably about – let me think – about 11 years ago. The DNA sequencing world really changed in 2005, 2006 with the advent of what we’re calling next generation sequencing. This was a real change and I spent most of the last eleven years knee deep in all of that ever since.
Dr. Smith: So it’s interesting, right? Genome sequencing, in and of itself, is something we can do, but that ultimately provides all kinds of information, right? So then the question becomes is how do we sort through that, how do we make sense of it, how do we apply that to medical practice? And that’s what you’re doing, right?
Neil: Absolutely, yeah. I think it’s safe to say we’re generating far more data than we know how to make sense of right now. With that being said, there’s an awful lot of things that we’re able to do with the data that we can generate --
Dr. Smith: Neil, let’s talk about that. Let’s walk through, a little bit, what you’re doing exactly at Children’s Mercy when it comes to genome sequencing and what are some of the current applications for it?
Neil: Sure. The place where we saw our initial and most immediate impact was in the area of diagnosing rare genetic diseases. This is really where we got our start as a center. The basic use case is that there are something like 4,000 or 5,000 genetic diseases that we know the genetic basis for. This is many more disease than a clinician can keep track of most of the time. Up until recently, the state of the art for sequencing for this diagnosis sis that a clinician would look at the symptoms, or dysmorphology of a patient and make a best guess about what condition to test for. The lab would then go out and test for that one condition and you got a positive result, or maybe you got a negative result. What would happen is a lot of patients would end up in what we’ve begun to call the Diagnostic Odyssey where they might go through many years and many thousands of dollars of tests without getting a molecular diagnosis. Genome sequencing changed that because what we’re doing is looking at, essentially all of the genes of the patients all at once, so that means we’re able to look at the whole landscape and find out what is really the diagnostic mutation. We initially got started with a small panel of about 500 genes, and then our center pushed forward and started doing whole genome sequencing. One really interesting use case was we developed an ultra-rapid, 50-hour turnaround, whole genome sequencing application that we were using for patients in the Neonatal ICU. The idea was that, for patients who are really critically ill, these are patients that might be able to make use of the very rapid turn-around. The diagnosis of rare disease is one of the biggest things that we’ve been able to do at the center. Since then, we’ve expanded out into using genome sequencing for cancer treatment and also what’s called pharmacogenomics.
Dr. Smith: Let’s get into that because that’s – being able to translate the sequence into the patient’s prescriptions and the treatment plan – that obviously is quite powerful. But before we do that, in the recent past, Neil, as a clinician, if I suspected what I’m seeing in my patient is linked to this gene, I would ask the lab to check that one gene. They would probably come back and say, “No, you’re wrong,” and then I would say, “Well, maybe it’s this gene.” It was a laborous [sic], laborious process to go through all this. Now, in doing the whole genome, we’re able – we’ve just sped up the process, right? Is that just kind of the gist of it?
Neil: That’s absolutely right. Another piece of the puzzle is that we’re able to take a symptom-based approach that lets us know what set of genes are most likely to be involved in the patient’s symptoms. Those two things together let us look at a whole patient’s genome and in a lot of cases come up with a very quick diagnosis.
Dr. Smith: That goes back – so let’s use an example -- If I have a depressed patient, we know that there may be certain genes, or certain polymorphism of genes that are associated with depression and so now we can test that patient’s genome against that database. Is that correct?
Neil: Yeah, that’s correct. What we would do would be to take the patient’s symptoms and come up with a candidate gene list and then cross-reference that with the result of their DNA sequencing. And like I said, around 4,000 or 5000 diseases, or genes, we’re able to know that a mutation in that gene is going to cause the disease. This helps, number one, with narrowing down diagnosis from 20,000 genes to the handful that might be implicated by the symptoms. It also lets us detect disease in cases where the patient isn’t presenting directly according the textbook. A lot of times patients haven't read the textbook.
Dr. Smith: Which mostly happens, Neil.
Neil: Right. A lot of times patients don’t know from the text book how they’re supposed to present. But looking at their genome, we’re able to see those kinds of things.
Dr. Smith: Let’s take the angle of prevention for a second because for me – I do a lot in preventative medicine – so for me, I look at this and I say, “Well, gosh, if I can know – Neil, let’s say that you’re my patient – and I can know at the get-go, what genes you have or what polymorphisms you have that are associated with depression and I say to myself, “Well, you have a lot of them so I need to protect you from depression as best I can, whatever that is.” Is that another application or is that opening up a door that maybe we don’t want to go down because just because you have a couple of the genes that are linked to depression, that doesn’t necessarily mean you will ever experience that in your life. Where do you see prevention in all of that?
Neil: That’s a really great point and I think that both aspects of what you’ve mentioned are things we need to pay attention to. I was talking about using genome sequencing for patients who are ill, but of course a whole genome sequence may have lots of applications to people who are otherwise healthy. Some of those might be looking at known risk alleles that would tell us that -- yeah in your example, the patient may be at risk of developing depression or heart disease. I think for the things that we know how to interpret, that kind of information can be really valuable over the lifetime of the patient. That being said, I think we need to proceed with caution and we’re only giving feedback on things we really know how to interpret.
Dr. Smith: What Is Astrolabe? I know that’s something that you’ve developed at Children’s Mercy, or you’re using a Children’s Mercy. Tell us a little bit about that.
Neil: Sure. Pharmacogenomics is another really great application of whole genome sequencing to otherwise healthy people. And what that is, is using the patient’s genomic information to inform drug selection and dosing. What Astrolade does is it’s a tool that takes output of whole genome sequencing and turns it into pharmacogenetically-relevant information that can then be used to help guide the selection of medications for a patient. With that, what we’re able to do -- for instance, there’s a common gene that’s called CYP2D6. This is a gene that is responsible for around 30% of all medication that’s prescribed. What we’re able to detect using Astrolabe and whole genome sequencing is that if a patient has a particular version of the 2D6 gene, we can predict that they are going to respond really well to a medication like, say codeine, or maybe they’re not going to respond at all, or maybe even they’re at risk of an adverse drug reaction or morphine toxicity because of the version of the 2D6 gene that we’re able to detect.
Dr. Smith: So this really helps us then to personalize really, what our – when the person does get sick we are able to personalize what those prescription choices will be and we have a better chance of being safe and effective with those medications. I guess in medical school now Neil, we’re going to have to teach pharmacokinetics, pharmacodynamics and now pharmacogenetics. We’re adding a whole class here.
Neil: That’s right. That continues to be a big challenge of pushing genomic medicine into clinical practice is how do we take information and make it most useful in clinicians who, as you said are not going to be experts in pharmacogenomics or pharmacogenetics.
Dr. Smith: I think that’s the challenge, right? Your everyday General Pediatrician, General Family Doctor, Internist, how—again, we just want to take care of our patients, right? We want to do what’s best. We want to get them back to their normal way of life and decrease the risk of anything happening again. It always becomes, how do I translate anything new into making that happen and I think that’s a definite challenge for something like Astrolabe and any genomic sequencing. Last question for you Neil, what do you think – and it’s a big question, I get it – what’s the future of all this?
Neil: That is a big question. I, personally, am one of the folks who think that whole genome sequencing is going to get more and more common until it’s a really routine part of healthcare. I think the promise of what we can do for personalizing care based on the whole genome means that we’re going to be motivated to tackle a lot of these really difficult questions of interpretation. And then, also all of the technical issues that are going to come around, how we manage whole genome sequence data, how we incorporate that into electronic health records, and how we make the best use possible for clinicians moving forward.
Dr. Smith: Neil, I’m going to ask you one more question – so I lied, there’s one more question –
There’s another field of study that’s growing too, which is epigenetics. Not necessarily looking at the specific genes, but looking at – what are the things that we can use, whether it’s supplements, foods, medicines, that can influence the expression of genes? How is epigenetics working with what you do in genome sequencing, or are they just two unrelated fields at this point?
Neil: No, I think they’re very related, of course. Epigenetics is tracking the effect of patient environment on expression of genes, like you said. If the genome is what’s there, epigenetics is – the expression might tell us -- how much of that is there. And I think moving forward that is going to be very important to making good use of this information. That being said, my personal opinion I think is that we’re not quite as solid with our interpretation of epigenetic data right now. We’re not quite as poised as we are with whole genome sequencing or whole exosequencing to make really good use of that in the clinical front line. It’s a huge research topic and one that we’re actually -- at our center -- we’re really starting to gear up to digging deeper into.
Dr. Smith: My guest is Neil Miller. He’s the director of informatics and software development at Children’s Mercy’s Genomic Sequencing Center. Neil, you’re in a great field. You’ve got a lot of work to do. You have job security, that’s for sure. That’s very fascinating work and I look forward to seeing what your center is going to – the things that are going to come out of it in the next few years. It’s very exciting to see the work that you’re doing. Hey, thanks for coming on the show. Great work. You’re listening to Transformational Pediatrics with Children’s Mercy Kansas City. For more information you can go to ChildrensMercy.org, that’s ChildrensMercy.org. I’m Dr. Mike Smith, thanks for listening.
Translating Genome Sequences into Patient Prescriptions
Dr. Michael Smith (Host): Alright, so our topic today is translating genome sequences into patient prescriptions. Neil Miller is my guest. He’s the director of informatics and software development at Children’s Mercy’s Genome Center. Neil, welcome to the show.
Neil Miller (Guest): Thank you, glad to be here.
Dr. Smith: I read in your bio here that Children’s Mercy sent over to me and I find it pretty fascinating what you do. I thought maybe we could start there, Neil. Just tell us a little bit about yourself, how you got interested in genome sequencing, and how that brought you to Children’s Mercy.
Neil: Sure, absolutely. My team is in charge of all of the bioinformatics analysis, high performing computing analysis, and software development in part of our Genome Sequencing Center. The backstory to all of that is just that DNA sequencing instruments produce an enormous amount of data, so you really need computational tools to make any kind of sense of it. I have now been at Mercy for five years – or almost six, now that I think about it. I was part of three folks who came from a small research institute in Santa Fe New Mexico, called the National Center for Genome Resources. We came to Children’s Mercy with the intent of establishing a genome sequencing center that would be integrated with patient care. We were trying to take a lot of things that we had done in a research context and really bring it to the front line in clinical care. I got my start in bioinformatics in the late 90’s, actually. I was introduced to the field as a software engineer and because of peculiarities in my skill set, I ended up out of the gate getting hired by a biotech company and that led to a position at the National Center for Genome Resources, where I was for ten years. It’s been a really interesting ride for me.
Dr. Smith: Right.
Neil: I got my start in genome sequencing, probably about – let me think – about 11 years ago. The DNA sequencing world really changed in 2005, 2006 with the advent of what we’re calling next generation sequencing. This was a real change and I spent most of the last eleven years knee deep in all of that ever since.
Dr. Smith: So it’s interesting, right? Genome sequencing, in and of itself, is something we can do, but that ultimately provides all kinds of information, right? So then the question becomes is how do we sort through that, how do we make sense of it, how do we apply that to medical practice? And that’s what you’re doing, right?
Neil: Absolutely, yeah. I think it’s safe to say we’re generating far more data than we know how to make sense of right now. With that being said, there’s an awful lot of things that we’re able to do with the data that we can generate --
Dr. Smith: Neil, let’s talk about that. Let’s walk through, a little bit, what you’re doing exactly at Children’s Mercy when it comes to genome sequencing and what are some of the current applications for it?
Neil: Sure. The place where we saw our initial and most immediate impact was in the area of diagnosing rare genetic diseases. This is really where we got our start as a center. The basic use case is that there are something like 4,000 or 5,000 genetic diseases that we know the genetic basis for. This is many more disease than a clinician can keep track of most of the time. Up until recently, the state of the art for sequencing for this diagnosis sis that a clinician would look at the symptoms, or dysmorphology of a patient and make a best guess about what condition to test for. The lab would then go out and test for that one condition and you got a positive result, or maybe you got a negative result. What would happen is a lot of patients would end up in what we’ve begun to call the Diagnostic Odyssey where they might go through many years and many thousands of dollars of tests without getting a molecular diagnosis. Genome sequencing changed that because what we’re doing is looking at, essentially all of the genes of the patients all at once, so that means we’re able to look at the whole landscape and find out what is really the diagnostic mutation. We initially got started with a small panel of about 500 genes, and then our center pushed forward and started doing whole genome sequencing. One really interesting use case was we developed an ultra-rapid, 50-hour turnaround, whole genome sequencing application that we were using for patients in the Neonatal ICU. The idea was that, for patients who are really critically ill, these are patients that might be able to make use of the very rapid turn-around. The diagnosis of rare disease is one of the biggest things that we’ve been able to do at the center. Since then, we’ve expanded out into using genome sequencing for cancer treatment and also what’s called pharmacogenomics.
Dr. Smith: Let’s get into that because that’s – being able to translate the sequence into the patient’s prescriptions and the treatment plan – that obviously is quite powerful. But before we do that, in the recent past, Neil, as a clinician, if I suspected what I’m seeing in my patient is linked to this gene, I would ask the lab to check that one gene. They would probably come back and say, “No, you’re wrong,” and then I would say, “Well, maybe it’s this gene.” It was a laborous [sic], laborious process to go through all this. Now, in doing the whole genome, we’re able – we’ve just sped up the process, right? Is that just kind of the gist of it?
Neil: That’s absolutely right. Another piece of the puzzle is that we’re able to take a symptom-based approach that lets us know what set of genes are most likely to be involved in the patient’s symptoms. Those two things together let us look at a whole patient’s genome and in a lot of cases come up with a very quick diagnosis.
Dr. Smith: That goes back – so let’s use an example -- If I have a depressed patient, we know that there may be certain genes, or certain polymorphism of genes that are associated with depression and so now we can test that patient’s genome against that database. Is that correct?
Neil: Yeah, that’s correct. What we would do would be to take the patient’s symptoms and come up with a candidate gene list and then cross-reference that with the result of their DNA sequencing. And like I said, around 4,000 or 5000 diseases, or genes, we’re able to know that a mutation in that gene is going to cause the disease. This helps, number one, with narrowing down diagnosis from 20,000 genes to the handful that might be implicated by the symptoms. It also lets us detect disease in cases where the patient isn’t presenting directly according the textbook. A lot of times patients haven't read the textbook.
Dr. Smith: Which mostly happens, Neil.
Neil: Right. A lot of times patients don’t know from the text book how they’re supposed to present. But looking at their genome, we’re able to see those kinds of things.
Dr. Smith: Let’s take the angle of prevention for a second because for me – I do a lot in preventative medicine – so for me, I look at this and I say, “Well, gosh, if I can know – Neil, let’s say that you’re my patient – and I can know at the get-go, what genes you have or what polymorphisms you have that are associated with depression and I say to myself, “Well, you have a lot of them so I need to protect you from depression as best I can, whatever that is.” Is that another application or is that opening up a door that maybe we don’t want to go down because just because you have a couple of the genes that are linked to depression, that doesn’t necessarily mean you will ever experience that in your life. Where do you see prevention in all of that?
Neil: That’s a really great point and I think that both aspects of what you’ve mentioned are things we need to pay attention to. I was talking about using genome sequencing for patients who are ill, but of course a whole genome sequence may have lots of applications to people who are otherwise healthy. Some of those might be looking at known risk alleles that would tell us that -- yeah in your example, the patient may be at risk of developing depression or heart disease. I think for the things that we know how to interpret, that kind of information can be really valuable over the lifetime of the patient. That being said, I think we need to proceed with caution and we’re only giving feedback on things we really know how to interpret.
Dr. Smith: What Is Astrolabe? I know that’s something that you’ve developed at Children’s Mercy, or you’re using a Children’s Mercy. Tell us a little bit about that.
Neil: Sure. Pharmacogenomics is another really great application of whole genome sequencing to otherwise healthy people. And what that is, is using the patient’s genomic information to inform drug selection and dosing. What Astrolade does is it’s a tool that takes output of whole genome sequencing and turns it into pharmacogenetically-relevant information that can then be used to help guide the selection of medications for a patient. With that, what we’re able to do -- for instance, there’s a common gene that’s called CYP2D6. This is a gene that is responsible for around 30% of all medication that’s prescribed. What we’re able to detect using Astrolabe and whole genome sequencing is that if a patient has a particular version of the 2D6 gene, we can predict that they are going to respond really well to a medication like, say codeine, or maybe they’re not going to respond at all, or maybe even they’re at risk of an adverse drug reaction or morphine toxicity because of the version of the 2D6 gene that we’re able to detect.
Dr. Smith: So this really helps us then to personalize really, what our – when the person does get sick we are able to personalize what those prescription choices will be and we have a better chance of being safe and effective with those medications. I guess in medical school now Neil, we’re going to have to teach pharmacokinetics, pharmacodynamics and now pharmacogenetics. We’re adding a whole class here.
Neil: That’s right. That continues to be a big challenge of pushing genomic medicine into clinical practice is how do we take information and make it most useful in clinicians who, as you said are not going to be experts in pharmacogenomics or pharmacogenetics.
Dr. Smith: I think that’s the challenge, right? Your everyday General Pediatrician, General Family Doctor, Internist, how—again, we just want to take care of our patients, right? We want to do what’s best. We want to get them back to their normal way of life and decrease the risk of anything happening again. It always becomes, how do I translate anything new into making that happen and I think that’s a definite challenge for something like Astrolabe and any genomic sequencing. Last question for you Neil, what do you think – and it’s a big question, I get it – what’s the future of all this?
Neil: That is a big question. I, personally, am one of the folks who think that whole genome sequencing is going to get more and more common until it’s a really routine part of healthcare. I think the promise of what we can do for personalizing care based on the whole genome means that we’re going to be motivated to tackle a lot of these really difficult questions of interpretation. And then, also all of the technical issues that are going to come around, how we manage whole genome sequence data, how we incorporate that into electronic health records, and how we make the best use possible for clinicians moving forward.
Dr. Smith: Neil, I’m going to ask you one more question – so I lied, there’s one more question –
There’s another field of study that’s growing too, which is epigenetics. Not necessarily looking at the specific genes, but looking at – what are the things that we can use, whether it’s supplements, foods, medicines, that can influence the expression of genes? How is epigenetics working with what you do in genome sequencing, or are they just two unrelated fields at this point?
Neil: No, I think they’re very related, of course. Epigenetics is tracking the effect of patient environment on expression of genes, like you said. If the genome is what’s there, epigenetics is – the expression might tell us -- how much of that is there. And I think moving forward that is going to be very important to making good use of this information. That being said, my personal opinion I think is that we’re not quite as solid with our interpretation of epigenetic data right now. We’re not quite as poised as we are with whole genome sequencing or whole exosequencing to make really good use of that in the clinical front line. It’s a huge research topic and one that we’re actually -- at our center -- we’re really starting to gear up to digging deeper into.
Dr. Smith: My guest is Neil Miller. He’s the director of informatics and software development at Children’s Mercy’s Genomic Sequencing Center. Neil, you’re in a great field. You’ve got a lot of work to do. You have job security, that’s for sure. That’s very fascinating work and I look forward to seeing what your center is going to – the things that are going to come out of it in the next few years. It’s very exciting to see the work that you’re doing. Hey, thanks for coming on the show. Great work. You’re listening to Transformational Pediatrics with Children’s Mercy Kansas City. For more information you can go to ChildrensMercy.org, that’s ChildrensMercy.org. I’m Dr. Mike Smith, thanks for listening.