Interview with Dr. David Smith, Mayo Clinic – Part 2

We just lately sat down with Dr. David Smith, Ph.D., one of the speakers at the Pageant of Genomics California right here in San Diego. This is part 2 of the interview. Part 1 could be found right here.

AllSeq: Driving down the price of sequencing has been the most important push for the NGS market up till now. Do you are feeling that is still the world that wants probably the most enchancment, or are different elements turning into more necessary? [Continued from Part 1]

Dr. Smith: I feel another impediment is that when any person is moving into this space, there are such a lot of questions they should ask. “What are the platforms that we need? What is the infrastructure we need? How do we analyze the data?” And there really isn’t a easy answer. A lot of the sequence providers promote machines. They don’t sell you a package deal that helps you’re taking these things and make some sense out of it, and that’s an actual drawback. That’s what I was hoping Qiagen was going to be. Here is a simplified integrated answer that you may purchase, only one set of issues that does every little thing. Nevertheless it has a few problems. I really like the thought but what they did is they ended up buying a sequencing [technology], sequencing by synthesis, that solely sequences that one end as a relatively low output and in consequence you’ve a machine that can just do actually, really small gene panels. It’s too small for anything but the smallest gene panels. In case you have ten, twenty genes I feel it’s fantastic. But when you get into an area like the neuropathies, there’s over 5 hundred genes which might be involved in numerous neuropathies – there’s no approach you can do it on the Qiagen platform, so they only have a few modules that they’re presently using. The platform is lagging up to now behind. Illumina has been out for over ten years in order that they have [released] dramatic improvements, but [the GeneReader] is only a new platform. I feel perhaps in time that Qiagen it might evolve into something like that, but I’m not too captivated with an integrated system that’s dependent on a sequencing platform that isn’t competitive at all with Illumina.

AllSeq: Do you assume medical sequencing shall be dominated by ‘point of care’ (POC) units or by extra centralized providers?

Dr. Smith: Nicely that’s a fantastic question. Now, it turns out that there are some technologies which are just about to return out which are going to have the ability to make these applied sciences extra (versatile) – you would send things out and you may have a handheld sequencer. The Oxford Nanopore was imagined to be that sort of an instrument. And certainly the great thing about it is the small footprint. That’s part of the rationale why they’re sending it off into area. The entire NASA factor is going to be doing sequencing in area, on those tiny little Oxford Nanopore cartridges. But proper now most of sequencing is completed even on the smaller footprint machines, on machines which are nonetheless comparatively costly, and consequently, proper now a lot of the sequencing is probably going to be achieved in a extra centralized style. In case you’re a place just like the Mayo Clinic, we’re going to definitely attempt to have the infrastructure here. In the event you’re a lab core you’ll do an analogous factor. Should you’re some of these smaller hospitals there actually but just isn’t an excellent platform that you possibly can just buy the machine and have every part you need. Qiagen is making an attempt to try this. Qiagen is making an attempt to have an integrated platform the place you buy two to 3 machines and also you principally have every thing from sample prep, library prep, small sequencing. After which on the back-end they’ve even bought the analytical elements. The thought is that you would have an entire built-in system and that system may over time be the type of system the place places that don’t have a large infrastructure might sort of do it. However I’d say that proper now and for the subsequent couple of years, I feel it’s nonetheless going to be dominated by the most important sequencing places and other people sending stuff out.

AllSeq: Do you assume using NGS will take off within the ‘direct to consumer’ area?

Dr. Smith: Oh it’s undoubtedly going to occur, it’s going to be a regulatory nightmare, and there’s going to definitely be loads of questions about what are the things that you’ll find. I visited an organization in England referred to as DNA Electronics. They are the ones that own the patents on the Ion Torrent platform. Jonathan Rotherberg licensed the patents, however DNA Electronics have been the ones who truly developed the patents. They’ve a small little system that’s handheld that you simply just put your blood or your sample at the very prime and it extracts it and it does the sequencing of it – that might be the type of thing that basically facilitates the thought of having this type of testing at residence. I might guess that in about ten years you’re going to have Japanese producing bogs that principally do some sequencing so you possibly can take a look at your microbiome every time you go to the toilet. That’s going to be essential for health and well-being.

AllSeq: You touched upon the differences between focused, exome and entire genome sequencing earlier [see Part 1]. Are you able to broaden upon that a bit?

Dr. Smith: Properly the choice on the Mayo Clinic is predicated on reimbursement, so the whole lot on the Mayo Clinic is small gene panels, because they’re very apprehensive about (getting reimbursed). However the reality is for the price level you’re truly better off to do an exome than to do a small gene panel. And my colleagues at Wash U., a variety of their medical checks, as an alternative of doing the small gene panels are exome-based checks. I feel that’s a better option to do it because you will discover more info, you’ll be able to develop highly effective databases because, once more, we’re at the very dawn of this period. I feel that the choices are usually not based mostly on what’s the greatest strategy. It’s based mostly on affordability and worries about reimbursing. It’s a rising number of small gene panels, and once I say small, some are twenty genes, some are five hundred genes, however all of these are relatively small, relative to the exome. In a perfect world, you wouldn’t do this at all. In a really perfect world you’d do genome sequencing, since you remove the cost of choosing for those issues that add a big value, and you discover much more info. How have you learnt what you need to search for is confined to the exome, which is lower than two % of the genome? We’re starting to discover how much of the genome just isn’t coding, and how necessary that is. You can also’t see structural modifications in the identical approach and you may’t see copy quantity variations. With genome sequencing, if it was low cost enough, you’d have the power to make sense out of all that knowledge. It might be the perfect means to take a look at these kind of issues.

AllSeq: An objection that we’ve heard from a lot of clinicians is that they don’t know the right way to deal with or interpret the info they’re getting back. They’re on the lookout for the only report that they will wrap their brains around.

Dr. Smith: Right. And even whenever you ship them outcomes from small gene panels, there’s means an excessive amount of info for them, info that they don’t even need. They need actionable info from the sequencing that they’ve seen. You’ve gotten one thing like Basis Drugs that looks at two to 3 hundred totally different genes however the actuality is, there’s only a small handful of those which are truly targetable. So that really supplies far more info than the clinician wants. The perfect can be whenever you sequence a small gene panel, an exome or a genome, you turn round and report back not all that info however simply what they should know (to answer the question) “What can you do for this individual?” And I feel it doesn’t matter how a lot info you generated. It’s the translation of that info and the visualization of data in a wise method, so the clinician could make an necessary medical determination. They don’t need an encyclopedia of variants. They only need to know the three or four necessary things that have medicine that they might use and goal it.

AllSeq: At the current Pageant of Genomics in Boston you have been part of a panel on the position of non-coding RNA in cancer. Principally we hear individuals speaking concerning the genome somewhat than the transcriptome. How would you price the significance of the two for medical purposes?

Dr. Smith: Properly the transcriptome is extremely essential. Again to what I used to be saying beforehand, in a super world with larger sequence output every thing can be entire genome sequencing, however entire genome sequencing nonetheless doesn’t inform you what’s being actively transcribed. So there’s undoubtedly the thought that in the future, perhaps it’ll be entire genome sequencing combined with some degree of transcriptome sequencing to get a extra complete picture. If we might make sense out of the methylome as properly then I might say in all probability all three applied sciences might probably be used. However there isn’t a query that transcriptome sequencing in the future is going to have a spot within the clinic, and there’s a whole lot of stuff in a transcriptome you could take a look at, but there’s also loads of stuff in a transcripome that we now have no clue what it means. In case you see a coding transcript, that makes more sense than should you see modifications in an entire collection of lengthy, non-coding transcripts of unknown perform. Finally with transcriptome sequencing you’re not only doing the quantity of transcription, you’re also wanting on the sequence of what is truly being transcribed. What do mutations, what do alterations, what do modifications in expression mean? Which isoforms are being produced is a large area and I feel that’s going to have an important medical significance, so one can’t discount the transcriptome. There’s an incredible amount of data that one can get hold of from transcriptome sequencing.

AllSeq: Have you ever seen transcriptomics being adopted within the clinic?

Dr. Smith: No, but there have been discussions. Genomic Well being was truly considering of transitioning into some kind of RNA sequencing as an alternative, however I feel they’re nonetheless sticking with their platform. Right now, I haven’t seen any medical purposes of transcriptome sequencing. They’re having hassle getting reimbursement for even the small gene panels, so addin this element will complicate issues. But there isn’t any query that it’s coming.

AllSeq: What are you seeing on the info evaluation aspect?

Dr. Smith: It’s the Wild West. Everyone is arising with totally different solutions. In case you’re simply starting to get into this, there are such a lot of totally different suppliers that offer you alternative ways to research the info. We played with that just a little and then started constructing our own infrastructure. Everyone is kind of on their own, and there’s no one that’s really risen to the highest. In contrast to Illumina, which is the premier platform for sequencing, there’s no premier analytical platform but.

The Pageant of Genomics has expanded into a number of places – Boston, London, and California. The subsequent event shall be held in London from Jan 30th – Feb 1st 2017.