Transcription:
Genomic Sequencing: The Good, The Opportunities For Improvement, And The Future

Dr. Michael Smith (Host): Our topic today is, “Genomic Sequencing, the Good, the Opportunities for Improvement, and the Future.” My guest is Emily Farrow. She’s the laboratory operations director for the Center for Pediatric Genomic Medicine at Children’s Mercy, Kansas City. Emily, welcome to the show.

Emily Farrow (Guest): Thank you, very much.

Dr. Smith: I love this topic. It’s fascinating to me. Let’s first talk about what do you think are the strengths of the next generation sequencing in clinical settings?

Emily: Next generation sequencing has really just exploded when we look in both the research and clinical world. The Human Genome project was just completed in about 2001, and so already, we’ve moved from taking ten years and a billion dollars to do a genome, to being able to do a genome for a few thousand dollars and to do it in as quickly as 20 hours if we need to. One of the things that that’s really enabled us to do, because of the decreasing cost of the sequencing and being able to put that – the sequencers have gotten smaller – so combining those together, we’re able to do genomic sequencing -- this next generation sequencing for lots of our patients now. It allows us – instead of looking at one gene at a time – so a patient would come in and we’d say, “Gosh, they look like they have – we think they have a specific disease, such as Marfan’s Syndrome,” and we would sequence that one gene. Then we would wait several weeks and come back and maybe have an answer, and maybe not and have to go again. Now, we can use this technology, and we can sequence thousands of genes at once, and it allows us to take a wider look at our genome and our DNA to get an answer more quickly for our patients. That’s one of the big strengths of that technology.

Dr. Smith: When we talk about that – it’s fascinating, right? Obviously, the technology is rapidly advancing, right? It’s making it hard for the general practitioner out there to keep up with this stuff, so it’s really nice having experts like yourself who can explain all of this to us. With knowing those strengths – being able to do this quickly, now and get that information quickly, what are some of the limitations, though, that you see with next generation sequencing?

Emily: Right, so it’s a little bit – it can be confusing, and the technology is hard to even for experts to keep up with sometimes. When we say, “Well, we ran the whole exome,” which is all the known genes, so we ran your entire genome, but we still think you need to do this other test, or we still don’t have that answer, that’s confusing, I think. It can be difficult for non-experts, and it’s also difficult for patients, and one of the things is the technology is amazing, but it’s honestly not perfect. One of the things that it’s not good at is if we look at human disease, we know it’s caused by different types of changes. What genomic sequencing is really excellent at doing is finding changes that are like misspellings, so single changes, or small changes in the genome. We know that some people have a disease that’s associated with bigger changes, so big pieces are missing, or extra pieces have been inserted into the genome, and that’s where genomic sequencing is not as good currently, is finding those big changes.

Dr. Smith: Yeah, so that’s an interesting way to think of it. When it comes to just the misspelled word, it can pick that up, but those big changes are hard for the sequencing to pick up. I’m sure that’s just a matter of time, right, when the technology catches up with that. You said something interesting. When you’re looking at the entire genome, and you’re looking at specific genes that may be mutated and may lead to certain diseases, etcetera, what about though – where are we at in really understanding how all of this works together? We know there’s concepts of things like epigenetics, and how different things like lifestyle, and medications, and supplementation, and all of these things can affect the genome. Where are we at in really understanding not just where’s that wrong gene, but how this all is interacting together?

Emily: Right, so I would say we’re probably still in our infancy. When we think of inherited syndromes, those Mendelian disorders, we’ve got a pretty good understanding for a lot of those, but when we start moving into more complex areas where there’s probably multiple genes that have changes that are working together, or it is a combination of your genome – or your DNA maybe puts you at a higher risk, but then you have an environmental exposure. Understanding where those risks are, that’s really still residing in the research world. There’s lots of exciting research going on both in functional genomics, both here at Mercy, and of course, other institutions. And also looking at more complex disorders where we think it’s multiple genes working together. There’s still a lot for us to learn. Genomics is really just getting started.

Dr. Smith: What about some of the other technologies that are used in conjunction with genomic sequencing? What are some of the other things that you’re combining with this to make it even more powerful?

Emily: As the technology is working, and as we’re working in development so that we can do all of these things with one test -- that would be the ideal thing is that we all just ordered one test to get it all. There are things that we can use currently to address some of the technological challenges that we see in sequencing. One of the common ones that we run at Mercy, and that other people also use, is something called an Exon Array. What that’s doing is it’s looking – it’s a specific test that’s looking for small deletions that we would miss by next generation sequencing -- so deletions or insertions that we won’t be able to see because of the way the technology works – but that also would be missed – they’re too small for, say, a standard microarray to catch. They’re kind of a donut-hole type of change that we’re missing. An Exon Array – often when you order a test, if you’re ordering something clinically and you see a reflex to a deletion-duplication test, you’re often probably getting that Exon Array in the background. They’re just not even explaining to you what kind of test that they're doing secondarily.

Dr. Smith: Right, but the ultimate goal, though, correct, is to have all of this done just through the genomics – like getting the genomic sequencing to a point where we’re not missing those things?

Emily: Absolutely. There’s some really exciting --

Dr. Smith: And that --

Emily: research applications and ones that are starting to move slowly into the clinical world where we would be able to get some of these copy-number changes, and misspellings that we’re getting currently with next-gen, all in one shot.

Dr. Smith: Right, so where the current genomic sequencing is good it’s where it’s finding that one gene where, like you said, there's that misspelling. The opportunities for improvement is catching those things, those larger deletions, etcetera that we’re now missing. Where are we really going with all of this, and I think that’s a big question, and I know that [LAUGHTER]. What do you think – where do you see, really, the power of genomic sequencing, and what does it look like in ten years?

Emily: When we think about the big precision medicine initiative that’s been launched, and you think about genomics, I think there’s really no better pair for that. I think where we’re moving to, slowly, and appropriately slow, is in ten years, in twenty years, whenever that time period may be, I think it’s going to be more common than not to have your genome sequenced. And part of the reason it will be more common is the price will continue to come down, but also, we’ll be able to interpret more. We’ll be able to look – so pharmacogenomics is a really important topic – looking to see how are you going to metabolize that drug? Your genome can tell us so that we give you the right dose at the beginning. That comes from your genome. Or knowing -- ultimately as we’re still working, we look at your genome, and we see you’re at higher risk, and now we can make these modifications. Or we look at your genome, and we see that this drug would work better. We see that already in cancer, particularly in adults, where you can target treatment based on the cancer genome. I think as we keep working, and the research catches up, we’ll be able to get so much information to help guide most appropriately your health management to you, and not just based on the average, which is what we do now, usually.

Dr. Smith: Yeah, so someday we will almost see – I can almost envision creating genomic profiles on all of us right from the get go. From the time that we’re born, understanding those things that we’re at risk for that we’re susceptible to, and being able -- it’s going to play a huge role in prevention, right? Don’t you see that, as well?

Emily: Right, exactly. There are several large NIH, nationally funded studies looking at genomes in newborns, and what are the benefits of doing that, and what are some of the risks, and what are the concerns that we need to address when we start moving down that path?

Dr. Smith: Emily, it’s fascinating work. I want to thank you for all that you’re doing. I know you must be working so hard to keep up and also to be innovative in the industry. Boy, you picked the right field to be in. Thank you for coming on the show today. 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.