Monday 23 September 2013

Monday morning thought for y'all...

No one innovates & disrupts by accepting the status quo, they do it by burning the text books & giving it a go! 

I had a crazy idea in my garage once and just thought I'd give it a go. It worked and now I have the coolest company in the world, QuantuMDx.

Wednesday 18 September 2013

Cancellation of the Archon X-Prize for Genomics


I appear to be on a rant roll… 

Why, oh why did the folk organising the Archon X-Prize cancel it? Rather than cancel it, they should have removed the entry fee. Only companies selling sequencing devices and services today can spare important R&D dollars for the entry fee. Unfortunately these companies technologies will never be able to even come close to achieving the criteria set to win the prize. 


Indeed, the criteria were set, rightly, to a very high level that only 4th or 5th generation, totally outside-of-the-box-out-the-door-down-the-road-over-the-lake-and-into-the-next-state technology will achieve. Therefore, rather than close the door on the prize, it should have been extended to allow for the development of this technology. It is not our (the next generation of sequencing rockstars) fault that the present old guard have limited their thinking and have settled with what they have got. 

Out of stagnation comes innovation… so reinstate it!!! 


Friday 13 September 2013

The Wonderful World of NGS (The Rant) - Part 2

And the rant continues...


The long(er) reads from Pac.Bio’s sequencer have shown the sequencing community (the 'Seqosphere' - I like dumb names, accept it) that long, single molecules reads must be the future of discovery genomics. Bravo Pac.Bio! However, whilst an awesome technology, some of the earlier chemistries demonstrated to the world that relying on biology and fluorescence have their limitations. Recent patents and grant applications suggest a move to the dark side for Pac.Bio. If only they could find a way to get rid of the enzymes, reduce the device costs & size, the bioinformatics burden and run times, then they’d be laughing.

The present excitement in the field, as we look to the future, is all centered on nanopore technology, which is, so far, promising to deliver a 'dream machine'. However, Oxford Nanopore Technologies (ONT) are apparently still relying on biological (lipid) membranes and proteins (reading a sliding window of 3-5bps) which is always going to give you stability issues and errors. Nabsys appear to have given up on nucleotide sequencing for now in favor of looking at structural elements (sounds a bit like the US Genomics story all over again) and Genia, well who knows where they are at other than they are able to make great microelectronic solutions. 


Yet, I applaud them all as they understand that the next generation needs to be another major step-change in sequencing. I further ‘doff my cap’ in their general direction, as what they are attempting is technically challenging, to the point of being close to impossible.


The concept of nanopores is a good one, direct read of single molecules over huge lengths. But the basic fundamentals of nanopore sequencing worries me somewhat (of course I’d say that, I’m not developing a nanopore sequencer, so am completely bias). The resolution isn’t there for true single base pair identification (as I mentioned above) and therefore the accuracy will most likely drop again. Moving to a solid state Graphene nanopore can theoretically solve this, but how long will this take to develop (recent noises from ONT suggest this is one research route the are pursuing at their base in Cambridge, MA). More importantly, there is only one detector, i.e. one shot at base calling (OK, two shots if you form a hair pin loop in the dsDNA and linearize it, or more if you oscillate it, which doesn’t necessarily get rid of the systematic errors associated with the method of base calling), so you’ll still be relying on sequencing many molecules to get the accuracy level right; ONTs ‘run until…’ approach.  


However, nanopore sequencing IS a paradigm shift and it IS truly stunning and we should celebrate companies like ONT and support them in any way we can! They are fighting enough battles with the technology development and the intense pressures venture capitalists give a company, they don’t need us, the Seqosphere, ridiculing them for delays that are normal for any hi-tech development project. Let us not forget Solexa telling us all in 2006, that their technology would sequence a human genome before the end of the year… "he just didn’t say which year" (as Harold Swerdlow famously said). Same thing is happening now with ONT. I think we’ll all agree that Solexa’s technology has done pretty well since finally sequencing its first human genome (well enough of it for people to say it was fully sequenced... it wasn't complete, no human genome has been fully sequenced).


When thinking about DNA sequencing using nanopores, I find myself wishing we could stack thousands of different nanopores on top of each other and have one DNA molecule translocate through the lot, with the sequence read as it passes through each nanopore. Why sequence thousands of molecules one time when you can sequence one molecule a thousand times? It stands to reason that a LastGen 2.0 technology (I call it this as Stefan Roever, CEO of Genia, once claimed their nanopore technology would be ‘LastGen’ Sequencing) would be able to do this, to directly read a single and whole chromosome thousands of times, in different ways in a single run. This will limit stochastic errors and weed out systematic errors. Imagine how important this tool will be for single cell applications, such as surveying the genomes of different cells within a tumor for instance.

Is this possible, sure, of course, it just needs some out of the box thinking, some money and a bunch of smart people to build it… it’s one of our internal projects at QuantuMDx, but surely we’re not the only group looking to develop the next gen, of the next gen, of the next gen… of the next gen of sequencers! We are going through the early stages of creating a novel technology for the field and it’s daunting. Our field is unforgiving of normal developmental hiccups such us early prototype error rates and delays in product launches. This resistance and sometimes mockery filters to the investment communities which limits companies abilities to raise the needed funds to make all our dreams a reality with the next big killer device.

So my call to arms is this; to all young scientists, senior scientists, P.I.s, institute heads and leaders of the bioscience industry, don’t accept the technological status quo, the bottom-line-driven fear mongering rhetoric of large sequencing companies who want you to believe their technology is the best and won’t be beaten whilst churning out diatribe to derail new entrants into the field. Do accept and understand that the funding-attracting sensationalism from fledgling companies claiming the $100 dollar genome with their “Last-Gen” killer technology is a necessary evil to lure investment dollars to produce killer new tools. Accept that the development of the next blockbuster DNA sequencing tool is hard, super hard, and that delays are inevitable and shouldn’t be mocked. Accept that venture capitalists insist on the dreaded ‘stealth mode’ to protect their investment from copycats. Don’t dismiss novel approaches and companies because they are not run by people with a track record in making sequencing tools, or you can’t immediately see how it can work. 

Dream of a world of high quality super long reads of single, whole chromosomes, telomere to telomere in a single rapid run, read out by cheap re-usable chips, Gattaca style. Help, advise and support these crazy innovators to make cheaper, faster, better sequencing technologies, because one of them may well deliver and the wonderful world of NGS will suddenly become even more fabulous!



Tuesday 10 September 2013

The Wonderful World of NGS (The Rant) - Part 1



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. 


Friday 9 August 2013

BBC Radio 4 - In Business, Gene Patenting

This is a very interesting debate and great plug for QuantuMDx Group Limited by our medical director Prof. Sir John Burn. I think Berwyn Clarke makes some valid points. This issue isn't as black and white as many people think. 

There must be a compromise!

"Ever since the mapping of the human genome was completed 10 years ago medical companies have been rushing to patent genes that define all of us for their own exclusive use. Now the US Supreme Court has ruled against patenting things found in nature. Peter Day asks what this means for the biotech business.and for the future of healthcare."


DNA Double Helix, courtesy
of BBC Radio 4

Thursday 8 August 2013

The QuantuMDx Story So Far - PART II




…. After the failure of our first business together, Elaine and I decided that we wanted to build a business of substance, rather than provide a service. This time the business was to be run and managed using our intuition, expertise and experience and not from any theories plied by a plethora of business schools or so called business experts. Above all the company had to be fun and motivating to work for. This was to be our baby and we were going to do it our way! 

The big idea...

Ever since my time at Harvard, I had been playing around with the idea of portable molecular diagnostic (MDx) and DNA Sequencing devices. I remembered reading in the Crimson about a Harvard Professor who had been able to detect the presence of DNA using tiny wires, or nanowires.

SEM of a bottom up nanowire
traversing two electrodes.
Detecting DNA using tiny silicon nanowires sounded like the coolest thing to me, more so that it was happening in a laboratory one building over from my lab.  I remember reading as much about them as possible and was honored to be at Harvard for the birth of such a great technology (and no, I am not talking about the Human Genome or Facebook, which also had its birth when I was there).

I delved into the literature and patents and ferociously read and absorbed as much as I could about them. It seemed clear to me that they where part of the puzzle I was constructing. Nanowire based biosensors can be produced in a standard CMOS fab, in great numbers and at low cost. They also operated label-free, without fluorescence, a big win as it meant that we didn’t need to use expensive fluorescent reagents or large and expensive detectors. Furthermore, they had been shown to have a ~10fM LOD and could be arrayed in their thousands (i.e. each sample could have 1000’s of tests done on it simultaneously). In short, it was the dream biosensor, multiplexed, cheap, scalable, super sensitive and small (perfect for a handheld).

The impressive wall of patents at Nanosys
As with most early stage companies in this space, securing your IP is the first job. We spoke to the great folk at Harvard Tech Transfer (one of the few university Tech Transfer offices that know what they are doing) and they put us in touch with a company in Palo Alto, CA, who had licensed all of Harvard’s nanowire technology.  I immediately flew out and pitched why they would want to exclusively license the nanowire technology to us in our field of DNA detection and sequencing. They agreed. Elaine followed up and negotiated a cracking deal for us and we used that to secure some initial funding that paid for the license.

We had a viable company!

A biosensor does not make a point of care (POC) molecular diagnostic device however, so with our license and the initial funding from an angel investor Julian (who has another role in Elaine’s life as private-life-husband. We joke that I am her professional husband as over the years we have had to spend a huge amount of time living together), we developed a coherent business plan, set up a laboratory in my garage (buying cheap equipment from e-bay among other vendors) and off we went.

The view from the 
Q-Apartment in Cape Town
Elaine went out and did the VC/Angel trail and held down several jobs to pay for the proof of principle data while I spent my days and nights testing technologies, ideas and reagents in my garage to pull together some initial proof of principle data that would support an argument for our vision of providing a multiplex MDx device. We incorporated the company on 4th March 2008 and on Xmas Eve 2008, whilst sipping champagne, we collectively signed the contracts on a multimillion pound investment deal from a state run investment fund in Cape Town, South Africa, for a joint venture.

QuantuMDx's lab in Tygerberg, SA
Part of the deal was that I would pack up, leave my family behind and move to Cape Town to set up the R&D facility and Elaine would set up the UK operations. So off we went and for 18 months it ran like a dream and we were very successful in all of our research and business.

Unfortunately one of the problems with government funds is that they can be taken away from you rather quickly and relatively easily. A reorganization of the regional funds saw a consolidation of not just the regional offices, but also of the projects they were willing to fund. We had demonstrated that we were on target and under budget, that our science was sound and technology was peer reviewed and viable, however they disputed the time to product that we claimed and as such we fell outside of their new criteria. It was a terrible day announcing the closure of the company and the imminent redundancy of the most amazing South African R&D team. The decision was hard to take at first, but in retrospect, that’s business and you just have to get on with it.

Elaine Warburton, entrepreneur
& business Rockstar!
And get on with it we did. I got back in my garage and started adding more data and wrote, with Elaine, some UK government grant applications. Fortunately, after going many months without a salary we successfully won one from i4i (part of the NIHR).

However, we still needed private investment to ensure we were a going concern and could provide the company contribution (UK grants are rarely 100% grants and require companies to match funds – a ridiculous situation that seems to favour larger companies). We walked the pavements of the city so many times and it was always the same story, too early, too late, too expensive, too inexperienced, etc, etc, a story I am sure most company owners will know well. It was soul destroying and utterly frustrating.

We were struggling with our finances, Elaine’s property was mortgaged to the hilt, mine was already in negative equity, all our savings had gone, the car was gone and we estimated that we were 11 days from calling in the liquidators, when we finally got our angel! Within a few days of successfully pitching to an a philanthropist we received a substantial investment hitting our account and we were back riding the rollercoaster! The deal was actually ‘inked’ over an iphone Skype call while Elaine and Julian were watching their youngest son score a 50 for County cricket. Rock n’ Roll!

Sir John Burn and I at the
Centre for Life
Upon getting the investment, our medical director (Professor Sir John Burn) managed to get us some space at the International Centre for Life in Newcastle upon Tyne, UK and I packed the garage lab into my car, along with some of my possessions and again left my family to pursue my dream.  I was kindly invited to stay at Sir Johns and once again built up the company from scratch.

We hired a few key positions, attracted more investment and grants (over £12m to date) and drove the development of our technology. As of today we have 40 staff (in 3 countries) working on our fully integrated bench top device that is capable of taking a whole blood sample through lysis, extraction, amplification and detection in under 15 minutes. Over the next 12 months we will miniaturize and speed up our bench top device so that it is palm sized and provides complex MDx analysis in under 10 minutes.


If nothing else, the above will tell you that we Quantumites (as we call ourselves) are a determined bunch and despite the shocking state of UK biosector funding, we don’t fail, nor will we fail in business or in our science. This blog will describe my personal journey as I ride the QuantuMDx rollercoaster. We are changing the world and saving millions of lives it really is that big!



The Q-Team outside our office


These are the personal words and opinions of Jonathan O’Halloran and do not reflect the opinion of QuantuMDx Group Limited.