Simon Barnett Profile picture
@ARKinvest / Genomics Analyst / Sequencing, Molecular Diagnostics, Bioinformatics / Chem+Bio Eng. @ Johns Hopkins https://t.co/W28MWl6K8V
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Jan 18 10 tweets 4 min read
Now that @Quantum_Si has given us a peek under the hood of its protein #sequencing platform (Platinum), we can begin comparing actual results to theory.

A few months ago, I shared this paper that gave a theoretical framework for protein sequencing:
pubs.acs.org/doi/10.1021/ac… The author simulated how different factors, such as the # of readable amino acids (AAs) and the read length, would affect a protein sequencer's ability to unambiguously detect the 20,000 canonical human proteins in our bodies.

That chart is attached below.
Dec 16, 2021 30 tweets 9 min read
A recent publication by Dennis Lo et al applied long-read sequencing (LRS) in the prenatal screening (#NIPT) setting. It's a rather unorthodox technology/application pairing, and it's got me scratching my head a bit.

Open Acces Link:

pnas.org/content/118/50… For context, earlier this year, Lo et al published a convolutional neural network ("the HK model") that enabled PacBio LRS devices to read methylation (5mC) across the entire genome with very high fidelity. This is important later.

What's methylation?
Dec 3, 2021 5 tweets 4 min read
@MJLBio @Sanctuary_Bio @Biohazard3737 Sure! I realize I was being a little vague with those statements. Generally, I think you're correct in your interpretation of the importance of P2 (great $/GB, but at a smaller scale) as well as duplex sequencing.

Something that is important to recognize, though ... @MJLBio @Sanctuary_Bio @Biohazard3737 ... is how product deployment works differently between PacBio and Nanopore, which is partly an artefact of culture and of time in the public markets, in the public markets. I'm not advocating for one over the other with my next statements.
Sep 16, 2021 28 tweets 6 min read
I'd like to share my initial reaction to today's Berkeley Lights report. But first, I need to do some housekeeping. I can't comment on stock movements, share financial projections, or debate fair value.

Please see our general disclosure: ark-invest.com/terms/#twitter Generally, I respect anyone who's put this much work into a topic. I won't pretend to have a clean rebuttal to every point. In my experience, beyond the hyperbole and hasty generalizations, there is some truth in these types of reports.

I want to soberly appraise those truths.
Sep 14, 2021 9 tweets 2 min read
What is lead-time bias in #cancer screening?

Imagine that a meteor was hurtling through space towards the Earth. Its speed and trajectory indicate that it will destroy the planet in approximately 10 years.

Now, let's say that our best sensors are only ... ... capable of seeing said meteor 1 year in advance. So, 9 years go by and we are blissfully unaware of our impending doom. Then, at the 9-year mark, we detect the meteor and measure our remaining survival time to be just 1 year.
Aug 17, 2021 14 tweets 4 min read
As short-read #sequencing (SRS) costs begin to drop again, undoubtedly fueled by a resurgence in competition, I suspect many liquid biopsy providers will add blood-based whole-genome sequencing (WGS) to supplement, or replace, the deep targeted sequencing paradigm. With a few exceptions, most clinical-stage diagnostic companies build patient-specific panels by sequencing the solid tumor, then downselecting to a few dozen mutations to survey in the bloodstream.

I don't think this approach is going anywhere anytime soon.
Jun 9, 2021 5 tweets 2 min read
We often discuss how more comprehensive and sensitive techniques improve the diagnostic yield for patients affected by rare genetic diseases. Indeed, yields have improved as we've gone from microarrays to whole genome #sequencing.

However, there's another critical component. Case-Level Reanalysis (CLR)

By reanalyzing genomic data, as our global knowledge-base grows, we improve diagnostic yields.

We believe the broadest tests should be done first to avoid the need to re-contact and re-accession patient samples.

ncbi.nlm.nih.gov/pmc/articles/P…
Apr 14, 2021 10 tweets 2 min read
The widespread adoption of liquid biopsy seems to be 'un-commoditizing' DNA synthesis in the molecular diagnostics industry.

Recall that synthetic DNA probes, molecules that bind and pull a DNA out of solution, are a critical input for liquid biopsy. Diagnostics companies buy probes to use in their clinical tests, oftentimes in bulk, from a synthetic DNA provider. There's been a prevailing notion recently that DNA providers only can differentiate on the basis of cost or turnaround time.

I think liquid biopsy changes this.
Mar 11, 2021 10 tweets 7 min read
@NatHarooni @snicobio I’m watching Jeopardy—will come back later tonight. Short answer—no, not competitive to PacBio. Likely friends down the road. @NatHarooni @snicobio Alright, so in theory the QSI platform can enable DNA (or RNA) sequencing on chip. However, I think of it more like a call option and less of a near-term goal. Proteomics is the killer app enabled by the QSI platform. But, as OP alluded to, multi-omics (inc. proteins) on one ...
Feb 22, 2021 4 tweets 3 min read
@NatHarooni @AlbertVilella In my opinion — HiFi reads are the most accurate/complete, but currently are more expensive and lower throughput. Nanopore reads are cheap, fast, and high-throughput, but have a weaker error profile. Both of these descriptors are changing and may not be the case in a few years. @NatHarooni @AlbertVilella As far as QSI is concerned, it’s a little too early for me to calculate operating costs per run. I’ll update when I know more.
Feb 21, 2021 7 tweets 5 min read
@nhawk45 @AlbertVilella Hey, @nhawk45 -- Sure, I think I can take some of these. Let's start from the beginning to help explain why certain features of QSI's approach/IP are needed and interesting.

First: Why are proteins the hardest molecules to sequence of the 'big three'? (DNA/RNA/Proteins) ... @nhawk45 @AlbertVilella Here are some of my notes on reasons I could think of, but I'll take a moment to elaborate on some of them.

The proteome is estimated to have the largest 'unit diversity' for lack of a better term. DNA = 20K genes, RNA = 10^5 isoforms, proteins = 10^6 proteofroms ...
Feb 18, 2021 11 tweets 2 min read
Anyone have any opinions on how self-insured employers consider innovative healthcare offerings to pass on to their employees?

As I understand it, by shouldering the financial risk, self-insured employers can curate a list of more relevant benefits ... (1/10) ... thereby avoiding paying out lofty insurance premiums for services that its employees don't use or want. There seems to be a long list of intangible benefits having to do with talent acquisition and retention, but I'd like to understand the cost equations more fully. (2/10)
Feb 17, 2021 17 tweets 10 min read
@TerraPharma1 @hiddensmallcaps Apologies for the incoming Tweet storm . . . @TerraPharma1 @hiddensmallcaps Here are some of my thoughts on the Personalis <> Natera tie-up. This is mostly a tech-focused breakdown, so not a recommendation to buy, sell, or hold any security: (bit.do/eyRo8)

First, a bit of background on the details and opinions scattered throughout . . .
Feb 17, 2021 4 tweets 1 min read
As cash-rich molecular diagnostics companies scale volume and expand menu breadth, there could be an "acqui-hire" shockwave.

These growing companies likely will continue vertically integrating in front (sample prep) and behind (informatics) to gain . . . (1/4) . . . operating efficiencies on the move up. Or, there could be a weak link in the existing R&D pipeline that needs mending all-of-a-sudden. For example, that extracting bite-size #epigenetic signal from blood would be central to earlier #cancer detection . . . (2/4)
Feb 16, 2021 6 tweets 2 min read
Interesting that Exact acquired Ashion (private) ostensibly to bring tumor-normal profiling onto the platform. This comes after they got exclusive rights to the TARDIS platform for MRD testing. Both Ashion and TARDIS come out of @TGen, so likely a smoother integration. Here's the original TARDIS paper: tgen.org/news/2019/augu…

Seems to be another form of error-corrected sequencing, which is useful for liquid biopsy applications where tumor fraction (amount of cancer in body) is very low, so this reads through to mutation-based early ...
Jan 13, 2021 10 tweets 3 min read
I've gotten a few questions about how the FDA regulates medical devices, chemical reagents, and diagnostic equipment.

Quick Thread 👇 First, understand there are two main regulatory pathways for diagnostic testing:

1. In-Vitro Diagnostic (IVD)
2. Laboratory Developed Test (LDT)

An IVD is an FDA-cleared diagnostic test sold as a self-contained kit.

thejournalofprecisionmedicine.com/wp-content/upl…
Jan 12, 2021 15 tweets 7 min read
JPM Healthcare Daily Roundup #JPM2021

The first day of the conference hasn't disappointed, especially if you're a fan of talking cubes. What is this mysterious object and what sorcery is inside?

See disclosures at the end. The Tempus One, meant to be carried in a doctor's coat or sat at the bedside, is a physical manifestation of @TempusLabs' genomic and phenotypic data-lake. Oncologists can ask One all sorts of questions regarding their patients, though I'm unsure if it'll (...)
Jan 10, 2021 6 tweets 3 min read
Tomorrow kicks off the JP Morgan Healthcare Conference, one of the most information-dense and exciting weeks for biotechnology.
#JPM2021

Though I’ll miss annual lab tours, I’m excited not to have my shoes destroyed amidst all the shoulder-to-shoulder crowds. Unlike last year, I’m going to try to give a daily news recap once the US trading session closes (inspired by @aurmanARK). My hope is to aggregate input from folks who can offer alternative takes.
Jan 5, 2021 31 tweets 10 min read
A Thread (🧵)

Let's discuss long-read #sequencing, optical mapping, and the implications of a recent study (linked below).

Please view my disclosures at the end. I've intentionally made this thread more technical as I think it's necessary.

biorxiv.org/content/10.110… First, let's deconstruct the paper's title: "De Novo Assembly of 64 Haplotype-Resolved Human Genomes of Diverse Ancestry and Integrated Analysis of Structural Variation".

De novo (Latin: "Of New") assembly involves sequencing a genome without the help of a reference.
Nov 18, 2020 15 tweets 4 min read
Long-read #NGS obeys Wright's Law.

For every cumulative doubling in sequence data generated across its install base, @PacBio has been able to lower (consumables) costs by roughly 30%, as shown below.

What could this imply about the future of long-read #sequencing? First, let's acknowledge a Catch-22. Does PacBio need to (a) derive knowledge from platform utilization to lower sequencing costs or (b) lower costs first in order to unlock greater platform utilization?

At present, we believe it's more of the latter. Why?
Oct 20, 2020 12 tweets 5 min read
Besides #immunotherapy, how can #CRISPR be used to treat cancer?

Researchers at @CNIOStopCancer just published an exciting proof-of-concept showing how CRISPR can delete cancer-causing gene fusions, selectively killing cancer cells.

I'll elaborate.

nature.com/articles/s4146… First, let's discuss what gene fusions are. As shown below, fusions result when two genes crash into each other and fuse together.

The resulting protein product is a hybrid. It has some features of Protein A and some of Protein B.

This usually is very bad.