A Short(ened) Note on Ion Torrent & High G+C

As one might guess from reading this space, I always have an itch to try new sequencing technologies or updates to existing ones.  That's generally a good thing in my position, though more than a few times I experience buyers remorse.  At least this time, I found something a bit interesting

Illumina's Blizzard

As the clear leader in the genome sequencing technology market, Illumina is often in the news.  As befitting the winter season, there's just been a blizzard of Illumina news, mostly announcements from within but also two important external ones (an excellent summary of these can be found at NextGenSeek).

Not Exactly the First Tuesday After the First Monday of November

This past presidential election was as nasty as any in recent memory, and so perhaps folks are reviewing their support for Churchill's dictum ("Democracy is the worst form of government, except all the others").  But, I make a plea now that you vote again.  I'll even extend that plea to a request that you honor a deeply held tradition in some urban political systems, which is to vote early and vote often!

In Vivo Blog follows the biotechnology industry, and now for the fifth year in a row they have a poll as to the best biotech deals in three categories: M&A, Alliance and Exit/Financing.  We've been nominated in the Exit/Financing category for our monster financing arrangement with Sanofi, which gives us a $120M runway so we don't have to worry about running out of money (a fate I don't wish to repeat ala Codon Devices).  So, please vote for us!

Okay, perhaps you'd like to objectively consider all the contenders.  The voting site has links to detailed discussions of each of the candidates, and I'm sure after reading each one that you'll be convinced we're the best, and you'll want to vote for us!

If that doesn't appeal, perhaps you like good old fashioned sibling rivalry?  At the moment, we have ground to gain on two other companies funded by Third Rock Ventures, bluebird bio and Foundation Medicine.  Both are fine companies trying to make important health care innovations.  FM was even started by our CEO, reinforcing their big brother status.  But, are any of them trying to reboot an entire sector of the industry that big Pharma nearly universally abandoned?  That sounds pretty courageous, perhaps even legendary.  So vote for us!

Sometimes a vote is strictly for an individual, but other times it makes sense to vote for a team.  We're a team worth voting for: unified in our quest, unbounded in our efforts. 

I'm Keith Robison, Principal Scientist for Computational Biology., and I approve this message.

MUSKET then FLASH, vice versa or just COPE with it?

It's gratifying to see that yesterday's The Trouble with FASTQ item gathered a number of lively comments, and there are certainly a number of branches I could (and should) take from that post.  But one item that garnered both a comment here and on Twitter was the order of operations I described

The Trouble with FASTQ

I spend a lot of time working with sequencing data, and the most common format for such data is FASTQ.  FASTQ has many things to appreciate, but FASTQ data also can be troublesome

Scribl is Neat!

Speaking of Twitter, one thing I've found it highly valuable for is discovering new tools and ideas in the bioinformatics space.  It's not a replacement for all my other methods, but I've discovered things I otherwise would have missed.  A great case in point is Scribl, which I discovered over the holiday period and vowed to try out this morning.  WOW!

BTW, I'm on Twitter

For a long while, my only interaction with Twitter was to monitor key hashtags during AGBT and ASHG.  However, I've gotten myself sucked in and am now actually contributing.  As suggested by the username OmicsOmicsBlog (archives at this link), I'm treating this primarily as an extension of this space.  So if you look you'll mostly find genomics, bioinformatics and other geeky stuff. I post more often, given that it's actually possible to author tweets on my smartphone (I once had delusions of writing blog posts there; it's really not workable). To date, I've retweeted more than I've originated.  It's certainly a challenge to compress thoughts into 140 characters.

I'm sure this has been covered elsewhere, but the 140 character limit is a weird holdover from text messaging, which itself was a weird technological cram job on the cellular voice standards.  What would Twitter be like if that limit had been higher or lower?

Why Next Gen Now?

A confession: I've considered writing this piece for a lot of years now; not quite as many as this space has existed, but many years.  Some ideas get stuck in my head, but I never force them out through my fingers.  Finally,with this one, I will pose the question: Why did "next-generation" sequencing happen when it did?

Nanopores: Fission or Fusion?

It's fall, and the foliage in New England is putting on its usual spectacular show.  What isn't showing is any of the progress in nanopore sequencing that I got caught up in last February.  Oxford Nanopore made quite a splash, and I wrote a quite breathless account based on a phone conversation with them.  Since then, other than raising some serious cash, Oxford has been quite quiet, and has neither released any data the community (or at least this blogger!) is clamoring for nor is there any sign that alpha units have been placed.  Genia was another nanopore company making noises about unveiling this year, but now they have licensed a new nanopore-based sequencing chemistry and promised boxes in 2014.   When will nanopores actually hit the market?

Does Illumina Have A Sequence Diversity Problem?

Roughly speaking, NGS sample preparation workflows can be split into two basic classes of workflows.  Complete molecule workflows are currently suitable for microRNAs and other small fragments at the moment, but attempt to capture the entire molecule.  With luck, long read technologies will someday make these the standard.  Fragment workflows are the workhorse, and take input material (RNA, DNA) and convert them into a library of fragments representing (or directly from) the original material. 

BGI Gobbles Complete Genomics

An email this morning alerted me that BGI Shenzhen is acquiring Complete Genomics.  I hadn't been following Complete's business very carefully and had missed (or forgotten about) their quarterly report in August warning that they were dangerously low on cash and had engaged a firm to look at strategic alternatives.  If you are holding Complete Shares (with the wonderful ticker symbol GNOM), you'll get $3.15 cash for each for them.  If you were unfortunate enough to buy them at the top, that's over $11 a share in capital loss to put on next year's tax returns.  I'm not one to watch stock prices closely.  Buy-and-hold an index fund is my primary investment strategy; A Random Walk on Wall Street is the best route to sound sleeping and good returns.  I've never held any GNOM stock.

Shameless cancer quacks

A news item meant to shock its readers caught my eye, but in the end I was shocked and sickened in a way that I think lay far beyond the writer's intent.  The writer's tale is of a desperate family of a cancer-stricken teenager being taken advantage of by a fame-seeking hoaxer; the tale I read is of a desperate family of a cancer-stricken teenager being fleeced by cancer quacks.

Is Cambridge Almost Full?

If you tour around the extended Kendall Square area of Cambridge, you'll find a number of large construction sites.  Various projects for Pfizer, Biogen, Novartis and more speculative projects are consuming most of the large surface parking lots in the area, and many that are yet untouched (such as the one next to Starbase Athenaeum)  are marked out for development.  There are a number of single story buildings, such as the bank by the Kendall T-stop, which seem likely to also become such sites.  However, on the outskirts of Cambridge just such a proposal has kicked up a serious hornet's nest, and one that suggests that the biotech (and tech) real estate boom here may soon hit a serious wall.

Farewell to a Giant Leaper

When I was a boy, a nearly annual occurrence was a trip to Kentucky to my maternal grandparents' house.  My biological grandmother died when I was quite young, but there would be many visits to see my grandfather.  I enjoyed them greatly, but of course he is now long gone.  So I have a few regrets, and mostly I wish I had thought to ask him a few questions.

Owning a Sequencer is NOT a Prerequisite for Sequencing!

Besides the little cancer genomics piece yesterday, another genomics paper getting quite a bit of popular press attention is the nice work from the NIH tracking down a deadly outbreak of drug-resistant Klebsiella pneumoniae, with 11 of 18 infected patients dying.  Rapid genome sequencing provided a much higher level of detail for tracing the outbreak than older methods, even distinguishing isolates taken from different sites on the same patient.

The Perils of the Too Small Gene Panel

The newswires are alive with summaries of an item in Science Express which, discounting the supplementary material, isn't much bigger than the news articles describing it.  It's a nice piece showing the relevance of cancer genomics, but there's also a backstory fleshed out in the news items which is interesting.

The gist of the paper is this: a trial of everolimus, an MTOR inhibitor, in bladder cancer did not go well; very few patients showed benefit.  But, one patient did spectacularly well.  So the researchers performed whole genome sequencing and found inactivating mutations in the well-studied tumor suppressors TSC1 and NF2.  Screening 13 more bladder tumors with a panel of cancer-specific genes found 3 more cases of inactivating mutations in TSC1, plus one patient with a missense mutation of unknown significance.  In the trial, patients with TSC1 mutations stayed on trial longer than patients without the mutations.  

My first reaction was "this all makes sense" -- TSC1 and NF2 are genes which immediately suggested themselves as TOR-related. 

What's interesting from the news items is a suggestion that the original patient had been sequenced for a limited number of genes around mTOR, and that this did not include TSC1 or NF2.  Of course, the problem when doing a limited screen is picking who to include, and from my 2 second analysis on the train I would have included TSC1 and NF2.  But, that could be much easier said than done.  They are attractive, since they are tumor suppressors known to be mutated in cancer, but so are other genes in the neighborhood (such  as TSC2 or PTEN).  There are activating mutations known in the neighborhood as well, such as PI3K or various AKT family members.  Presumably it was a PCR-based (quite likely Sanger) method, in which case it can be challenging to target every exon both because you may have an "exon budget" (number of exons to be amplified) and some exons are nightmarish to amplify.  

I think the case illustrates one reason whole genome or whole exome sequence are by far the best strategies in a case such as this.  The potential payoff in understanding is huge, as you have one strong outlier patient.  The number of patients are small (though, admittedly, this is probably one success pulled from many dry holes).  Plus, these days the cost of WGS/WES is probably not much more than targeted PCR, given the costs of developing good PCR assays.  

The other potential advantage of WGS/WES, over even broad cancer-specific gene panels, for a case such as this, is that the field can change.  New oncogenes and tumor suppressors are identified periodically, perhaps even in the time period between when a panel is designed and it is used.  In a research setting to understand the basis of a clinical trial anomaly, it's particularly valuable to explore all corners, because what might not make sense today might become clear tomorrow.

Jackalopes & Guest Posts

Recently, the topic of jackalopes showed up at work.  Anyone who has toured the American West has probably come across postcards of these curious beasts, with the bodies of jackrabbits but antelope-like horns.  Even out East, at some frequency reports of these creatures appear stochastically.

An unconvincing case to X-out algebra

I had a bit of a long commute yesterday, driving from south-central New Jersey up to Starbase Cambridge.  In general it's a dull ride, having been done too often.  Still, it was the perfect time to absorb the magnificence of a George Washington Bridge crossing, followed by a great sunrise-lit view  from the loop ramp onto the Henry Hudson Parkway, and similar snippets of the Palisades also glowing in the early sun.  But, much of the time I was flipping through radio stations.  Due to this, I caught the tail end of a NPR interview with Andrew Hacker, who wrote a recent NY Times opinion piece calling for algebra to be removed from the required high school curriculum in the U.S., which has garnered letters both for and against.

Complete Genomics Goes Long

In Nature this week (as an open access article!) is a report from Complete Genomics and collaborators describing CG's new "Long Fragment Read" (LFR) technology for generating long range sequence information and haplotypes.  Technically, there is a lot of cool stuff -- but excitement for many (such as myself) must be balanced against CG's business model of sequencing only human genomes

Qiagen Buys A Sequencer

Today's news (take your pick of Bio-IT or GenomeWeb for original stories) is that Qiagen has bought out Intelligent Biosystems (IBS), the company in nearby Waltham developing a platform using sequencing-by-synthesis chemistry licensed from Columbia University