A thousand apologies for the month between
posts, however I have been bouncing around different cities speaking at
conferences and meeting potential investors for QuantuMDx (I shall discuss this
in a later post). During my travels I
have spent a lot of time thinking about DNA sequencing technology and why I am
so frustrated with the field in general.
So I thought I would treat you all to
a rant, lucky you…
Highly parallel shotgun sequencing (i.e.
breaking up the chromosomes in to short fragments and sequencing, from either
end, 25-400bp+ nucleotides, before assembling all the short reads into
contiguous sequences and then ordering the contigs into a scaffold along a reference
sequence) is great, but can never provide a true and full de novo genome sequence, which is required for the next phase of
discovery genomics. It should instead be focused to perform targeted
re-sequencing for clinical applications and newer technologies developed and
optimized for discovery.
Short read parallel targeted sequencing tools
are OK for exome sequencing, as there aren’t many repeats in coding regions and
as ~80% of all [inherited] disease-causing mutations are located within protein
coding regions, many researchers and clinicians appear happy with this.
However, for discovery, the fact that we are unable to resolve ~20% of disease
causing variation, means it's not the tool for discovery (I am sure this is not
news to most of you) and in the future, not even the tool for the clinic. What about
structural variation, repeats, CNVs, centromeric and telomeric regions. These
are important and as we’ve been accepting mediocrity in our sequencing
technology for so long, we know very little about them, as we’ve been unable to
sequence them.
Sure highly parallel shotgun sequencing can
get us so far with genome sequencing and will certainly maintain it’s position
as the dominant force in ‘whole’ (note: we have still not sequenced a complete
human genome, nor are we able too with presently available technology) genome
sequencing, blah blah blah. However, it’s not as great as we all thought it was
when 454 & Solexa released their initial visions. We (genome scientists) deserve
better than that, we’re bloody smart people, yet here we are accepting imperfect
technology.
Short reads suck, assembling to a reference
genome sucks more, missing out on important structural variation is scandalous.
Why are we investing so much time and effort into making our sequencing and
bioinformatics tools incrementally better? Isn’t that just accepting the status
quo, essentially telling all budding young scientists that we’re giving up on
technological innovation so that we can polish a turd…. C’mon people wake up
and smell the asparagus (a random ‘23&me’ reference, if you’re now
scratching your head and thinking I’ve lost the plot)?!?!
Yes, I'm spouting histrionics to make a point, shoot me!
It is the technology that's lacking at the
moment. So we should focus on ways to build better devices that can read long
fragments of single DNA molecules (preferably whole chromosomes, from telomere
to telomere), directly, without relying on error prone enzymes, or reporter
moieties and labels (move away from the ‘light’ people and join the dark-side…
pH too for that matter) and with significant redundancy in the system to weed
out stochastic and systematic errors!
These technologies exist today; they exist in
the heads of scientists and in the labs of small companies vying for investment
dollars. So why don’t we invest our time, money and efforts in helping &
supporting them rather than drinking the shotgun-Kool-Aid and deriding the
brave souls attempting to make the dream sequencer.
1 comment:
A short, cool and concise description of the sequencing field status indeed.
I do agree. We should focus on developing tools to fill the gaps left by current technologies. Perhaps on complementary technologies that can be used together with the current shot-gun methods and making these cheaper at the same time. That is perhaps the best compromise between the need to improve the current method and the demands from today’s business world.
So its hard to find this middle term that is both good for the scientific community and good for investors as well. Its also demanding, as it puts a lot of pressure on everyone involved in R&D, as you certainly know. But we humans do have the ability to do great things, as long as we work hard and don’t sit in the shadows of our previous achievements. We also have the ability to be creative, finding clever solutions to current problems such as this one.
I do have the pleasure of working with some of the best minds in the field, so I’m also trying to challenge the status quo. It’s hard, it’s demanding and its also frustrating, as the investment community is very reluctant to support change, at least if its not web based apps. So the extra pressure goes to people like you and me, the visionaries, the thinkers, the darers, and, hopefully, the doers.
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