[samchorlton]

So happy to see this here. While sequencing is quite old, mass adoption still has not come. The benefits are clear - faster infectious disease diagnosis, personalized treatment, tracking the spread of infection, identifying food contamination - the use-cases are endless. However before nanopore sequencing came, it was always out of reach of the masses.

We've actually started BugSeq[0] to help labs get into nanopore sequencing - improving these open source tools and also writing our own. Orgs like FDA, USDA, big food co's, CDC, etc are now all adopting nanopore sequencing. Happy to see the industry taking off, this will be a step function improvement for public health in general.

(disclaimer: founder of BugSeq) 0: https://bugseq.com

[dekhn]

personalized treatment is still best handled by gene panels. nobody has made a compelling argument for WGS for personalized med. Right now it's a huge waste of investment until we understand the multigenicity of diseases better (which is a research problem best solved by sequencing millions of individuals and using high quality WGS sequencers).

[samchorlton]

We work within the infectious disease space, so I'll give an example from our work that is still personalized medicine: Faster detection of antimicrobial resistance. Every infection will be resistant to different antibacterials/antivirals/antifungals/antiparasitics. What if we could get the patient on the right antimicrobial for their specific infection faster? There's strong evidence that timely administration of correct antimicrobials in septic shock results in improved mortality.

Nanopore sequencing very much has the potential to deliver this personalized treatment, without looking at any human genes or panels. If we could rapidly sequence bacteria in the bloodstream and predict their antimicrobial susceptibilities, we can make a difference.

[dekhn]

What you're describing is a very reasonable research topic with some supporting evidence.

What I'm saying is that nobody has delivered on any of the huge claims about the genome which genomicists made for the last 20 years, specifically in terms of actionable human health.

it's time to start calling the bluff.

[samchorlton]

I'm not exactly sure how you can say that.

The following have been revolutionized by the human genome project and subsequent technological innovation in sequencing:

-Non-invasive prenatal diagnostics

-Screening for cancer with cell-free DNA

-Rapid and accurate diagnostics for children with suspected genetic disorders

-Targeted cancer therapeutics

Many of these are already in routine clinical use in high income countries and result in significant improvement in human health.

[dekhn]

The impact is minor and most of the progress did NOT come from HGP data.

I worked in genomics for 20 years. I have deep knowledge of biology and medicine. And the reality is, for the amount of money invested, the actionable medical returns have been relatively tiny and industry continues to not invest in sequencers for a good reason.

[acmj]

> the actionable medical returns have been relatively tiny and industry continues to not invest in sequencers for a good reason

I agree with this, but I disagree with the following:

> most of the progress did NOT come from HGP data.

Without HGP (Human Genome Project), many biological discoveries in the past two decades would have become much more difficult.

> it's a huge waste of investment until we understand the multigenicity of diseases better

If you don't invest, you will never approach a solution. Applied science goes nowhere without a solid foundation in basic science.

[abcc8]

None of the techniques you describe are reliant on WGS. I wholeheartedly agree that sequcning has revolutionized medicine, but WGS isn't there yet.

NIPT uses low-coverage sequencing to identify aneuploidies for chromosomes 13,18,21 and some larger microdeletion syndromes - this is not WGS.

Cell free cancer screening is panel based and assays specific, known driver mutations.

Rare disease diagnostics can be WGS based (and some of the rapid 48h WGS studies of NICU babies are compelling from a technical standpoint) but most diagnoses identified via WGS can also be found via WES + chromosomal microarray.

Targeted cancer therapeutic target identification is panel based for most patients, as WGS doesn't identify too many targets for FDA-approved therapies that a panel + IHC + FISH + fusion testing won't.

[searine]

>What I'm saying is that nobody has delivered on any of the huge claims about the genome which genomicists made for the last 20 years, specifically in terms of actionable human health.

I mean. Sure, sequencing the human genome didn't solve our problem overnight, and you can't sequence a genome at a vending machine for a nickel to tell your future, but I think there has been an avalanche of medical data derived from the genome and that is only continue to get bigger.

Now that we are really starting to figure out the polygenic risks and the single deleterious variants and their links with phenotype, people will have a much better picture of what their future might hold (and how to prevent it).

I don't think it was ever a bluff. The problem just turned out harder than we thought it was going to be.

[dekhn]

it didn't turn out to be harder than I thought it was going to be. I came into this in the 90s fully prepared for the idea of polygenic risk. In my opinion, most people who did molecular biology first think that way, while most people who learned mendelian genetics don't.

I had my genome sequenced a few years ago by Illumina. They had a big slick presentation, blah blah blah, ApoE1, etc. When the genetic counsellors came to my genome they said "huh. you don't have any risk factors". I checked and each of their risks was from an existing gene panel, so the WGS wasn't valuable (it's on PGP, if you want to work with it https://my.pgp-hms.org/profile/hu80855C).

I talked in more detail with the counsellors. Turns out, whenever they saw a novel variant that wasn't covered by a gene panel they were googling the variant and skimming the abstracts of papers.

It was at that point I realized the difference between research, PR, and actionable medical data.

[searine]

>it didn't turn out to be harder than I thought it was going to be.

Fair.

I've done my as well. Most of the "company" sites don't tell you much, which I think is a legal thing. They aren't cleared to release clinical predictions from genotypes, so they just... don't. I ended up running my through promethease (which mines SNPepedia) and found quite a bit more than what was reported.

I work with some certified clinical geneticists and yeah they do take a much closer look, but at the end of the day its all just sequencing and interpretation. I think its mostly just safeguards to keep bad actors at bay.

PGP looks interesting. I see that you submitted phenotype data. I didn't know they had a questionnaire with that. That's actually really interesting. I need to see what kind of questions they ask.

[et2o]

This was a talking point like 10 years ago which isn’t remotely true today

[salt-licker]

Sounds like the mission of Day Zero Diagnostics (dayzerodiagnostics.com). Are you working with them?

[et2o]

“nobody has made a compelling argument for WGA for personalized med” is a huge overreach. It’s done routinely now at most academic cancer centers and often is useful for guiding treatment decisions. There are several multi billion dollar companies that do this already.

[teekert]

One example: Homologous Recombination Deficiency, the signature it leaves genome-wide and the associated sensitivity to PARP inhibitors.

But agreed, it is about time we start to understand regulatory regions better. But that will require gathering more WGS data, and indeed most data is Whole Exome or Panel.

[dekhn]

Research project, not actionable human health. I fully support large-scale WGS projects and hope that some day one of them will have a recognizable impact.

[samchorlton]

I don't know about this specific example, but DNA sequencing is already routinely used for personalized oncology therapeutics outside of clinical trials, so not really research project.

Source: Am MD and practice laboratory medicine.

[dekhn]

Sure. Doctors love to try new technologies. most of the reports of success are happy narratives, not evidence based medicine.

[et2o]

There are hundreds of clinical trials and it’s used today in clinical practice, most commonly in oncology but more and more in other fields. Very interesting work in polygenic risk prediction models in many kinds of chronic disease, where risk models can refine treatment strategies. It’s very real; one of the big problems so far has been reimbursement and commercialization.

The other thing you have to realize is that because of the regulatory burden, it takes a while for these tools to make it into practice. Many of the successful genetic tests today were approved 20 years ago. Look up Oncotype Dx which is used in a huge % of breast cancer surgery, for example. WGS and WES will undoubtedly be far superior but it takes a while to get these things into practice.

[samchorlton]

Except when it makes it into guidelines written by groups of experts aggregating evidence. I can't copy due to copyright but hope you can find the content past paywall or peruse the citations: https://www.uptodate.com/contents/next-generation-dna-sequen...

[tonto]

The development in the article is basically gene panel using nanopore sequencers. It dynamically ejects sequence that doesn't match the thing the user is interested in programmatically

[nextos]

I think typing your HLA class I and II genes is the single most valuable thing you can get now from your genome. It's also pretty likely to remain extraordinarily valuable even if whole-genome sequencing prices drop to nearly zero.

HLA associations with autoimmune disorders are extraordinarily strong. Same applies to infectious diseases, vaccine efficiency and checkpoint inhibitor efficiency.

While you can type HLA with classical techniques, the only really reliable way is really to use long reads.

Same applies to CYP enzyme superfamily, where variation is linked to some rare drug toxicity events for example.

We should all know our HLA and our CYP genotypes. Why 23andme does not even attempt to impute HLA is beyond my understanding.

[heuermh]

Totally agree! I would suggest adding KIR as well. Curious what your background/interest is?

I have consulted to National Marrow Donor Program/Be The Match [0] off and on for several years. There are typing labs using long reads but most reporting/matching/analysis is still performed at the nomenclature level [1].

I hope in the near future we'll be able to simply assemble the entire MHC for each sample, as messy as it might be, see e.g., "A diploid assembly-based benchmark for variants in the major histocompatibility complex" [2].

[0] https://bethematch.org [1] https://www.ebi.ac.uk/ipd/imgt/hla [2] https://www.nature.com/articles/s41467-020-18564-9

[nextos]

Sure! KIR and HLA-C are also really important.

But we know less associations about them. Same applies to TCR genes. A chicken-and-egg problem, we need good massive GWAS to find out.

My background is in CS, AI and statistics. But I've done lots of graduate research in genetics and epigenetics. I'm very interested in understanding the interactions between HLA and commensal / pathogen epitopes in health & disease. Also in vaccine design.

How about you? I can see from your posts you are with the Big Data Genomics team at UC Berkeley AMPLab.

[ngcc_hk]

All great until this was used for people control. Collecting dna which you cannot control and even can trace your race or relatives.

We have internet. Great. But look at the dark side. DNA is great like target medicine but you have totalitarian regime which might use it.

Need some sort of awareness. How to deal with the two sides, let us discuss once you know there is a very dark side to it.

[samchorlton]

Thanks for your concern. All technologies come with benefits and risks. Of course, DNA sequencing can be used for harmful purposes, eg. tracking individuals. We should be very cautious of these risks as the technology develops, and take well thought out steps to mitigate them. A similar analogy can be made to the internet and tracking people. Overall, however, the benefits of DNA sequencing to society already far outweigh these risks.