We recently sat down with Dr. David Smith, Ph.D., one of the speakers at the upcoming Festival of Genomics California here in San Diego. Dr. Smith, a professor in the Department of Laboratory Medicine and Pathology, wears many hats at the Mayo Clinic, including running a lab where he works on the characterization of the common fragile sites in the genome and on the role that human papillomaviruses play in the development of a variety of different cancers.
AllSeq: Amongst your many roles at the Mayo Clinic, you’re the Chairman of the Technology Assessment Group for the Center for Individualized Medicine. Can you share with us your perspective on how the genomics market has been changing?
Dr. Smith: For about ten years I was the chairman of the research Core Oversight Committee, which was a committee that oversaw the various research cores at the Mayo Clinic. And it was that that point in time that I really became knowledgeable not just about genomics but also about how the technologies themselves have improved. We do have a lot of genomics facilities, but there’s also mass spectrometry, bioinformatics, flow cytometry, and things like that. But about eight or nine years ago I became the chairman of the technology assessment group at a point in time when we actually got our Center for Individualized Medicine up and running. So the technology that I’m most interested in, because I think the technology that is going to be the most transformative, has to be genomics-based technologies. And it’s not just the next generation sequencing, but I think a lot of them are centered around that because that’s a technology that can replace so many other things. We’re starting to see that even things like cytogenetics are going to be replaced by a sequencing-based technology. Cytogenetics is actually transforming from classical cytogenetics to array CGH and that seems to be the platform. But very quickly that’s going to transform to sequencing. So my role as the chairman of the technology assessment group, and I’ve been doing this pretty much since I think the whole next generation sequencing revolution started, is to see the various manufacturers that produce the platforms for sequencing. But it’s not just sequencing because obviously you need to isolate nucleic acids. You need more and more robotics for the preparation of the libraries and, very importantly, after you do the sequencing you need to have the necessary infrastructure to take all that information, assemble it, make some sense out of it. Then you need to be able to translate that back to the clinician, and the last component is you need the necessary technology to take all that data and store it. So all of that is a big part of the whole component of what sequencing has become today.
AllSeq: NGS is starting to be adopted in the clinic, with NIPT, cancer and rare childhood diseases being the first examples. Where do you think we’ll start seeing NGS adopted next?
Dr. Smith: Wellness. You keep seeing this stuff now where, especially now that we have the Olympics coming up, where they’re going to start to think about how you can use these types of technologies to better inform our elite athletes what’s the best training program. That translates down (to the general population) – I’m a long distance runner – I’ve run a lot of marathons. So that whole group of individuals certainly are going to want to have this information so you can have your training programs centered around your genomics. And I think that’s going to be a huge area and then that’s going to translate to the general population. We’re sort of seeing it already with these tests that you can take at home, like 23andMe and things like that. It’s simple information about your heritage but eventually it’s going to get to the point where that information helps you to decide what are the best training programs, what is the best diet, and things like that. So I think that is a huge area, but it’s an important question that you ask because I can’t think of an area that won’t be impacted by this revolution. Right now we’re seeing – just as you said – this stuff beginning to be translated into the clinic, but the reality is it’s going to happen in all aspects of clinical practice. Cancer is a good first place to start because it’s a low hanging fruit. We spend so much money for cancer treatments that most of the time don’t work. Look at the enormous savings we can have if we just get a little intelligent about it. But the reality is that cardiovascular disease, neurodegenerative disease, obesity, diabetes – across the board – is going to be completely transformed by these technologies over the next couple of years.
AllSeq: How far along the adoption curve do you think we are for clinical next generation sequencing?
Dr. Smith: Well it is already being adopted, there’s absolutely no question about it. If you go back five years in time there was absolutely no next generation sequencing as any component of clinical practice. And today, certainly in the Mayo Clinic, but in so many other places as well, more and more tests are transforming clinical practice. Five years ago I’d say all the molecular genetic tests were PCR and Sanger sequencing based. They’re starting to realize how much more powerful next generation sequencing is. Why look at one gene and then go through that and look at another gene the whole diagnostic odyssey when you could just make a panel of genes, or what I’d recommend, which would be the exome, to look at everything? So I think it is definitely being adopted, but the question is, “where are you?” Because if you’re at the Mayo Clinic or you’re at any one of these very large places, I think it’s already occurring. If you’re a small regional hospital and smaller places than that, it’s about to be implemented but it hasn’t happened yet.
AllSeq: What are the biggest factors preventing NGS from being more widely adopted in the clinic?
Dr. Smith: Well there are a number of things that are really slowing this thing down. It’s hard to say what is the number one, but it comes to the top of my list as this overall issue about reimbursement. And we certainly feel it here, but a lot of places do as well because they’re doing these tests and they’re wondering do they have codes for the various things, or what type of reimbursement can we get? But that’s just one of the problems. A real serious problem, and Mayo Clinic has it and a number of other places do as well, is that this technology isn’t just the purchase of a sequencing machine. It’s the building of a giant infrastructure that has the necessary machines, that has the necessary expertise to run the machines; more importantly, has the necessary expertise to take the data from the machines and make some sense out of it. And finally, you have to have some way to translate that sensibly so that you can inform a clinician exactly what to do. You can’t send somebody an encyclopedia of variants and say “you figure it out.”
AllSeq: Driving down the cost of sequencing has been the biggest push for the NGS market up until now. Do you feel this is still the area that needs the most improvement, or are other factors becoming more important?
Dr. Smith: There is a need, but there isn’t the available technology. Now people like Thermo Fisher don’t like to hear this. Certainly people like Pac Bio and Oxford Nanopore don’t, but we live in an Illumina sequencing world. Illumina completely and totally dominates the sequencing space. I think that’s a tremendous disservice to the entire effort, because with the absence of competition Illumina is under no pressure to improve anything like output or customer care, and those are important considerations. The output on these machines is incredible compared to where we were just a few years ago. But over the past year to two years there hasn’t been any real dramatic increase in output because Illumina has absolutely no competition. They look back and they see nobody behind them, and they may make the false claim that people don’t want more sequencing or more output and that’s actually wrong. People actually do want more sequencing. Everyone talks about the $1000 genome, and it does cost less than a thousand dollars on the biggest Illumina machines to do a genome sequence, but that’s not the full cost of a genome sequence. A genome sequence is how much it costs to sequence, to assemble, to interpret, and to store. And if you put all of those things together, right now, we’re probably in the era of the $5,000 genome, not the $1,000 genome. So, in reality, actually there is a need for greater sequencing output. I personally think the $100 genome is a better target, and once you get to there, why can’t you have a $10 genome, because that will actually drive the entire market. And that will also totally transform the nature of the sequencing that we do. The reality is, that with the notable exception of NICU (neonatal intensive care units), there is relatively little whole genome sequencing, clinically. It’s just too much information, it’s too much to assemble, and there’s too much difficulty in determining what it means. But if we could have the genome sequenced for less, then I think the whole market of the small gene panels – the exomes – will absolutely disappear, and that will become the way the genome is characterized.
But there are a lot of things that definitely need to be improved. In the ideal world, in an absolute ideal world, what would be fantastic would be to have machine like what the Pac Bio machine was supposed to be. They claimed ten years ago that could give really long reads, that it could give really high sequence accuracy, that had tremendous output for a very low price. But we’re miles away from almost all of those targets. So what we’re left with is a world where you are talking about 100 to 300 base pair sequences, and from the Illumina platform. And what could have really improved that is a couple of things: greater sequence output so that the actual sequencing costs less. But I think that right now the biggest thing, and everyone talks about this, is the analytical bottleneck. How do you take that information, how do you translate that information, and do something with it?
In part 2 of our interview we’ll touch on additional topics, such as POC and DTC sequencing, targeted vs exome vs whole genome, and more.
You can catch Dr. Smith at the Festival of Genomics California, which is being held in San Diego for the first time. The Festival will be held from September 19th – 21st and offers free registration for the main sessions. Be sure to check out their BaseCamp for workshop opportunities.