Wednesday, November 30, 2016

Is PromethION a Strategic Error?

Be prepared for another burst of Oxford Nanopore coverage; their annual Community Meeting in New York City begins on Thursday (perhaps while you are reading this).  I won't be attending; only so many absences from the day job are ultimately feasible each year, and I've long since hit the limit.  Hopefully some prolific tweeters will keep everyone updated, and I can summarize from there.

As with most posts on Oxford Nanopore, my piece on the closure of the Illumina litigation captured some comments; I think it is reasonable to expect more on the piece on the opening of litigation by Pacific Biosciences.  How you perceive the ambiguity around whether they were using an MspA pore in the R6 and R7 chemistries or not tends close to a Rorschach test.  But with that behind us, attention can focus on their current state and progress. Now, I'm going to project some critical ideas around one of their platform pieces, but I have no delusions that they will affect Oxford's course.  It wouldn't shock me if Clive had a tart seven letter response, the only question being if the last three letters form a pronoun or a preposition. I don't have any inside information nor do I have any direct financial interest in the company, in case you are wondering.  As my title suggests, what I'm going to argue is the case that pursuing the launch of the PromethION instrument is an unnecessarily risky detour.

Tuesday, November 29, 2016

Revisiting Mendel

In yesterday's post, I flagged a small factual error in Siddhartha Mukerherjee's The Gene.  I really liked Mukherjee's prior history of cancer, The Emperor of All Maladies, and was thrilled when Dr. Mukherjee wrote a thoughtful response to the criticisms I did make.  So it was another happy moment recently when he asked me if I'd like a copy of the book so I could review it.  I'm only about a third through the book, but it is definitely worth reading (why did I wait so long? no good reason).  Since I like it, when I get to a full review I'll probably be mostly in "this is what I would have suggested if I were an editor" mode.  I'm not ready for that yet (finishing the book is a pre-requisite!), though cryptic notes are piling up in my Evernote on the topic.  However, there is a specific part of history covered in The Gene which warrants separate treatment, using the book more as a springboard than as the central subject.  That concerns the amazing man widely regarded as the founder of the science of genetics, Gregor Mendel.

Monday, November 28, 2016

Nostalgic for Fly's Eyes

Kumar Thangdu's mission of prodding me has contributed to a bout of nostalgia for one of my graduate student rotation projects.  He asked in a tweet how I'd allocate funds if I was given stewardship of a billions in grant money.  If you want to get some big results but are willing to be very patient, then a great way way to invest is in model organisms.  As a rotation student at Harvard, I spent several months pushing Drosophila melanogaster, the not-so-humble fruit fly.

Wednesday, November 23, 2016

RNA-Sensing USB Stick: Promise Despite the Hype

Earlier this month the newsfeeds were abuzz over a new USB-stick style nucleic acid testing device. Based on technology from the United Kingdom firm DNA Electronics, this device is intended to make testing for infectious diseases portable and inexpensive.  Since the pulse of news was triggered by a publication in a journal, I dove in to see where things really stand.  The device is interesting, but alas the paper describes a prototype far from ready to deploy.  Also interesting to ponder is how this device might stack up against other devices emerging for the portable diagnostics marker, such as Oxford Nanopore's MinION.

Monday, November 21, 2016

News from Old Neighborhoods

Five years ago, the initial band of scientists at my current employer had just moved from the offices of our venture capitalist sponsor, Third Rock Ventures, into lab space in Cambridge sublet from Blueprint Medicines.  The Athenaeum Building is a large brick-faced building which once held the publishing house by that name.   Eleven Biotherapeutics was trying to engineer new immune-modulating proteins, initially focusing on a treatment to dry eye.  Some of their IP I understand was pulled from the wreckage of Codon Devices.  Also on the floor was Verastem, a company spun out of work from Robert Weinberg and Eric Lander on cancer stem cells. In the last few months, major news has been announced by Third Rock, Blueprint, Eleven and Verastem which illustrates many of the forces that make life in early discovery interesting (as in "may you live in interesting times").

Sunday, November 20, 2016

Will Liquid Handling Robots Ever Join the 21st Century?

In the course of this blog, there are many topics I've thought about writing that I haven't touched.  Sometimes it is due to the problem of the topic being too revealing to what I am working on, sometimes it is because I'm not satisfied with the result, but far too often I procrastinate so long that it no longer seems fresh.  Or I'll just do it another time when the moment is right, which it never is.  But a recent Twitter exchange reminded me of a long-suppressed lament on some expensive, finicky and problematic -- but very useful -- denizens of a modern lab: liquid handling robots.

Thursday, November 17, 2016

HGP Counterfactuals, Part 7: Wrapping Up

It's been interesting revisiting a bunch of now ancient history of the Human Genome Project with the goal of exploring other possibilities.  I started by considering the entire concept of alternative histories, then reviewed the construction of physical maps, strategies which were considered for sequencing the clones comprising the minimum spanning map of the genome and the actual sequencing technologies employed, then considered scenarios in which no HGP is launched or the project is given a much smaller budget and forced to focus on technology development.  Tonight, I'll close this out by trying to summarize some of the ideas that came out through this process, as well as some further thoughts on the whole exercise.  Plus some references to the two megaprojects to which the HGP is often compared, the Manhattan Project and Project Apollo.

Wednesday, November 16, 2016

HGP Counterfactuals, Part 6: Ax Sharpening Only

At the beginning of this series, I promised two alternative histories on the Human Genome Project.  Yesterday I explored a timeline in which opponents of the HGP successfully kept it from ever being funded.  Today, I'll try to imagine what would have happened if the project had been funded only to develop new sequencing technology.  One warning: as part of this I will show the most reviled plot in genomics, but to make something other than the usual point.

Tuesday, November 15, 2016

HGP Counterfactuals, Part 5: HGP Stifled

Okay, enough procrastination. I've outlined the general idea of counterfactuals and then obsessively detailed the generation of physical maps, planning the sequencing of BAC clones and the rapid winnowing of sequencing technologies during the early stages of the genome project.  Time for a main act: what if the public Human Genome Project never happened?

Monday, November 14, 2016

HGP Counterfactuals, Part 4: Sequencing Tech Landscape Circa 1992

In this series leading to a pair of Human Genome Project alternative histories, I've been warming up with a trio of analyses of the technology landscape.  At first I couldn't decide on the order to post these in, but then it was clear to me: a progression of scale from physical maps of the genome to how to organize the sequencing of the BACs, and now to the actual sequencing technologies which were in play.  In particular, how there was a very rapid evolution from 1992 (when I first was deeply exposed to this angle by attending Hilton Head) to 1997 (when I defended, but also the outcome was clear).  In this time period, a large number of possible options essentially compressed to a single one: automated fluorescent dideoxy sequencing.  That outcome was not clear in 1992

Sunday, November 13, 2016

HGP Counterfactuals, Part 3: BAC Sequencing Strategies

I introduced this seven-part series with an exploration of the values and challenges of counterfactual histories.  Yesterday, I looked at the "forgotten maps" which laid out the genome ready-to-sequence as a minimum tiling set of BACs, made sure that those BACs faithfully represented the genome and that this set was tied at regular intervals to the genetic markers and cytogenetic locations which were the linga franca of human geneticists.  Today, I'll look at strategies that were considered for sequencing all those BACs.

Saturday, November 12, 2016

HGP Counterfactuals, Part 2: The Forgotten Maps

Yesterday's post explored the concept of alternative histories, or counterfactuals and laid out why they might be a useful way to think about the value of the Human Genome Project.  In this installment, I'll explore what I will call the forgotten maps, the critical elements of the HGP which are all too easily forgotten.  These were both critical and expensive components of the project, so forgetting them is a mistake.  Their prominence has faded as new technologies have come in and subsumed them, or they were mostly means to the end of a first human sequence, but understanding the project requires understanding these forgotten maps.  And I will admittedly cover only a few; I'd invite anyone familiar with the ones I don't illuminate to remedy my failings (a careful reading of the Nature paper on the physical maps wouldn't be bad either).

Friday, November 11, 2016

HGP Counterfactuals, Part 1: An Introduction

My new correspondent, Kumar Thangdu, has posed some challenging questions with regard to the Human Genome Project.  He's been good enough to capture my initial tweet stream over at his blog, which was my initial defense.  I then followed up with my note on my one paper in proteomics, which I received favorable feedback on  from one of my co-authors.

Thursday, November 10, 2016

Oncology: The 10Km View

My Twitter correspondent Kumar Thangdu keeps throwing interesting but difficult questions my way, far faster than I can keep up.  Not sure I'm even particularly skilled at many of these.  But, one must try.

Friday, November 04, 2016

Homopolymers and Other Recurring Topics in Pore Taste

Some interesting comments showed up on my piece covering Pacific Biosciences trade action launch against Oxford Nanopore.  Alas, some silly comments showed up as well.  Life on the Internet.  In particular, Mohan Chennupati asked a series of questions that can be seen as more friendly to PacBio and less so to Oxford Nanopore than my analysis.  They're all good questions and worth digging into, and you'll find some other commenters addressing them.  I'll quote from his comments but rearrange the order a bit.  I believe I've not changed their meaning or damaged his argument, but please check me.  The main reason I've rearranged is that one of the comments is the one I find most interesting, so I'm saving the long answer on that for the end.

Thursday, November 03, 2016

PacBio's Quixotic Patent Litigation

I'm feeling very glad I closed out the Illumina/U. Washington litigation vs. Oxford Nanopore the other night, albeit very belatedly, as now Oxford is facing a similar set of legal actions, but this time initiated by Pacific Biosciences.  PacBio has filed a complaint with the U.S. International Trade Commission (ITC) alleging that Oxford is infringing on an issued U.S. patent, 9,404,146 (aka 146 Patent).  Surely PacBio's management thought this was a good idea, but from this perspective