Genetic Signatures for Superbugs : Scarily Irrelevant

I will confess it has taken me several days to write this post. Not because I’ve been too busy – indeed, I have spent many fruitless hours staring at my computer screen trying to motivate myself to write this post. Normally there is something that get my juices flowing. Either I feel a sense of disdain for something that a company has done in the marketplace, or there has been a ridiculous claim made about a technology … or even yet another pointless clinical trial update. After about 70 posts, I’m still far from hitting a “Jon Stewart level” of disillusionment with my own peculiar and warped brand of satire, but some days it is genuinely difficult to get a rise out of myself.

Especially since this blog will not end until every single ASX-listed healthcare company in that Long Tail is covered at least 2-3 times – which incidentally means that I am faced with the prospect of writing about the same shitty companies again at some stage in the future. It is a truly herculean task, akin to climbing up an Everest-sized steaming dung-heap, barefoot and without oxygen.

For me the big challenge comes when I look at a company that doesn’t even belong in the decade we live in, and Genetic Signatures (ASX : GSS) – a molecular diagnostics (MDx) company – is just such a firm. GSS is the biological equivalent of someone walking into Steve Jobs’ office in the heyday of the iPod era and saying “I’ve got a new technology you need to look at, Steve, I call it the transistor radio.” It’s like posting a billboard on the side of the Sydney Opera House, purporting the health benefits of cigarettes. It’s like Porsche releasing a new model of the 911 Carrera with a coal-fired, mid-mounted, pressurised steam engine. It’s like our venerable political leaders taking the stance that gay marriage is unconscionable and unacceptable in Australian society, and ultimately leads to bestiality.

Oh wait, that last analogy is still apparently relevant.

Sorry. Please Disregard. 

Cory Berndardi Bacteria

A colleague of mine (one of those annoyingly bright PhD types with a blabber mouth to boot) described it best. I must confess I was tempted to simply steal his soundbite, but because I am sort of an honest chap and because you will immediately realise that it is cleverer than anything I could have possibly come up with on my own, I will not take credit :

It is like these guys are marketing the latest Lamborghini. But to show you how good it is, they do not compare it with last year’s Lamborghini but instead compare it a shopping trolley harnessed to a litter of small piglets.

Brilliant.

Honestly, I just don’t know where we would be without car analogies.

The actual reason that I have struggled to get this piece out is because it all boils down to giving a science a lesson, and that isn’t quite so much fun as mocking people for their stupidity. To be clear, the market potential for molecular diagnostics in an era where infectious diseases are one of the major threats to human health, is vast. Technology developments are taking place at a breathtaking speed to predict epidemics, manage widespread hospital infection, combat the potential of bio-terrorism and develop new solutions for the very real threats of drug-resistant bacteria. The problem is that GSS isn’t going to contribute one iota to that momentum and I would like to explain why.

At the heart of GSS’s technology position is the concept of converting all the cytosines in a strand of DNA (or RNA) to methylcytosine, and then deaminating them to turn them into thymines. The result is that instead of the need to process a whole lot of AGCTs (the four base pairs of a DNA strand, if you recall your high school biology) in whatever “detection system” you want to use, you only need to process a bunch of AGTs (a “3Base” system) and this reduces the information density when trying to identify the “genetic” signature of a particular kind of pathogen.

I have illustrated this below:

GSS Chemistry Primer

The GSS team correctly claim to be pioneers in bisulphite chemistry but honestly, given that this is true, I just don’t understand how this company could then make the outrageous innovation claims that it does. But let’s back up for a minute and talk about some of the basics of this chemistry and the various contexts in which it has been studied. Firstly, DNA methylation has been researched for a couple of decades now, and more recently (you know, like a decade ago) became part of a powerful toolbox for the development new biomarkers for a wide range of diseases, including cancer. The technique is powerful because it helps to identify pieces of our genome that are most susceptible to mutation, with methylation patterns potentially diagnostic even for specific disease subtypes. Indeed it is reasonable to argue that the understanding of this fundamental bit of biochemistry has helped to create the entire field of epigenetics, that’s how much science has been done in this area in the last 2-3 decades. I make this point to highlight that the scientific foundation of GSS’ technology “differentiation” is not an obscure area of research born out of a lab somewhere in Western Australia. In fact, understanding DNA methylation/deamination (including the fundamental developments of bisulphite chemistry) is over 20 years old, spanning back to the day’s of Frommer’s fundamental work, with bisulphite sequencing considered to be an established method (if less important with the advent of high-throughput sequencing technologies).

Now while Dr. Melki was probably still wearing his high school togs and snogging girls behind the bike shed when the original work was being done (and from the looks of his GSS website photo, that may have not been all that long ago), most of the rest of the grizzled and gnarly team certainly wasn’t. Sir Greg (awesome guy, love him to bits) is certainly “long in the tooth” enough to be able to identify a true innovation in this space and Dr. Millar certainly is, because he was one of the first guys (along with Frommer) to use bisulphite-induced modification of genomic DNA for genomic “mapping”.

Twenty three years ago.

So why are we still talking about this as though it is a new discovery?

As for the deamination of amino acids, the biological importance of this is also not a new discovery. In fact, spontaneous deamination of 5-methylcytosine is the most common and fundamental single nucleotide mutation in nature. It’s one of the reasons why astrobiologists look for ammonia signatures on distant planets as a possible indicator of life.  In fact, the entire biochemistry (above) has been known by humans in various guises for at least half a century. However depending on your religious beliefs, there is an even crustier lab rat behind this biochemistry – called God, Allah, Yahwh, Jehova – whatever. This “technology” that GSS is spouting, has been naturally occurring on Earth for at least 3.8 billion years, ever since the most primitive organisms were lolling about in some stinky, steaming primordial soup.

So what of this amazing technology that re-codes a genetic sequence from 4 bases to 3 bases?

Well, back in the day when you might have been cranking away dutifully at your PCR machine, doing heroic primer chemistry to characterise a few strands of DNA, complexity reduction might have been interesting to think about. Indeed, that was one of the reasons why the identification of DNA methlylation sites was originally so interesting – it enabled you to intelligently identify “hot spots” that might be of biological significance instead of trawling through the whole damned genome. Frankly, two decades ago, anything you could do to achieve some sort of genome complexity reduction got a lot of attention. And, of course back in the bad ‘ol days, when working with the genomes of infectious disease organisms, one needed to culture enough material to be able to do the biochemistry, so the whole thing took a lot of time, effort and cost. But the pace of technology evolution has been breathtaking and today we have such vast improvements in technology platforms for sequencing DNA/RNA (and the cost has plummeted) that, quite frankly, nothing new in PCR is all that interesting anymore.

GSS’ innovation would have been big news in 1992. Honestly, it’s sort of like Dr. Millar went into a coma for 20 years and then woke-up and thought “dammit, I am going to start a company.” At least if you are going to make the claim to be the guy that revolutionised PCR for pathogen detection, be as interesting and crazy as the LSD-fueled psychopath who discovered the original PCR “Lamborghini”. Don’t calmly and rationally tell us that getting rid of cytosine makes all the difference.

Of course, the truth is, we don’t use high-end genomic sequencing to do routine detection of infectious diseases. We will one day, but we’re not quite there yet. In the meanwhile, nature gave us a much simpler way of detecting all those nasties. Ironically it was precisely the study of bacterial genes using some of the above-mentioned research tools that led to the understanding that the easiest “fingerprint” for infectious disease detection are conserved genes. The result is that we have an excellent and efficient (“reduced complexity”) framework for detection and phylogenic characterisation of bacteria, for example through the use of 16S ribosomal RNA gene segments. This has lead to an innovation explosion in the development of techniques and devices for bacterial pathogen detection because we can now use simple oligonucleotide probes to detect and classify bacteria, right down to a single-cell level if necessary. It can be done using label-based methods like FISH or flow cytometry, but also novel surface chemistries, materials and conjugation techniques have enabled the development of sophisticated label-free methods (sorry, couldn’t resist the plug) that can work with great sensitivity/specificity on cell lysates without any need for culturing.

Gosh darnit, obviously the boyz at GSS haven’t been talking to the surface chemistry wizards at ADO

A phylogenic map of bacteria based on conserved genes (source : Nature)

A phylogenic map of bacteria based on conserved genes (source : Nature)

The bottom line is very simple. There are a plethora of ways to detect bacteria – some are old fashioned but proven (like PCR/RT-PCR) – and some are exciting new platform technologies that will ultimately transform infection management. Some clever boffins at MIT are even exploiting the use of bacteriophages to do whole bacteria detection, which is an obviously intelligent thing to do and yet another example of how Mother Nature is smarter than Homo sapiens. Today, PCR is still a standard approach that is widely used (and it works perfectly ok without GSS by the way). Yes, you don’t actually have to use sophisticated probe-based approaches for many simple applications, for example the IDI-MRSA assay works just fine. Contrary to GSS’ claims, we don’t “wait days” for culture anymore for something like MRSA testing. In fact the only reason we continue to culture for positive microbe identification under certain circumstances is because of “best practice” infection control protocols, although RT-PCR has more or less addressed this issue for PCR-based assays.

To conclude, this is an irrelevant company with an irrelevant technology and I can’t believe it managed an “oversubscribed” IPO. What an embarrassment. This doesn’t mean that GSS can’t produce a product that ultimately sells well (though please don’t get me started on the commercial realities of channel strategies and competitive dynamics for MDx technologies), but the differentiation isn’t going to come from the GSS’ “3Base” technology, I promise you. 

I am actually a big believer in building integrated clinical solutions, where workflow, throughput, sample/reagent usage, etc. is optimised and I would mostly rather use a product that works well, than a product that had some super-proprietary science but didn’t move the needle in terms of performance. It may very well be that the team at GSS has a product that labs love and that’s ok. But to make the claim of a proprietary technology that enables an outcome, hereto unrealised, is utter bullshit. I don’t care how many big name scientists you put on your advisory board, or your ability to roll-out your buddies from Cambridge to lend their well-earned academic credibility to your underwhelming value proposition, I am not buying it.

5 thoughts on “Genetic Signatures for Superbugs : Scarily Irrelevant

  1. Hi Chris

    I am somewhat surprised your “PhD type with a blabber mouth to boot” thinks GSS is a late model Lambourghini. Personally, I would have thought it is more a Ford Prefect or a mid-70s, kack-coloured Datsun 180B with a peeling vinyl roof (my first car and the memory of which still brings tears to my eyes).

    I am glad I am not alone in trying to understand the Orwellian logic of “3 bases good, 4 bases bad” from these guys. Intuitively it does not seem to make a lot of sense in that there are always conserved regions that can be targeted and there are now really good algorithms for designing primers to be as discerning or promiscuous as you could ever hope. I mean, if we are able to target drugs to the incredibly shapeshifting landscape that is the influenza virus, I can’t see that it can be all that difficult to design primers that will will pick up multiple strains of various pathogenic microbes.

    The one thing that has always confused me about GSS is why they never provide data showing that they can achieve things with their 3-base system that cannot be done with 4-base templates. I mean, isn’t this the very first experiment you would do…like way back whenever you thought this was a good idea. It wouldn’t be that hard to do and really makes it hard to dismiss the most obvious explanation.

    That being said, I am not surprised that their IPO was over-subscribed. Not because this was a poker red-hot investment opportunity that everyone was throwing every spare dollar at. No, not at all. Quite simply, every IPO is over-subscribed. They just are. Admittedly sometimes by one, single, lonely share that will spend the rest of its life wondering why it bothered…but you only need one.

    But one thing that gets my goat (and I don’t mean that in the Greek way) is when companies downsize their IPOs/raisings several times (as GSS did) and then come out saying this seriously whittled down and sub-scale capital injection was over-subscribed. No it wasn’t. You just put it into that machine that was in “The Fly” to make it look bigger than it really was.

    Admittedly, I do something the same thing whenever I need to lose weight; just zero the scales with 20kg on them an voila, Mr Slim and Slinky walks out of the bathroom.

    PS. You still owe me two turds.

    Liked by 1 person

  2. I think it was $7.5M…and that was partially underwritten by their major shareholder….which doesn’t sound off the klaxon in terms of overwhelming demand.

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  3. “….and that isn’t quite so much fun as mocking people for their stupidity.”

    This -and comments like this- really detract from your blog Chris. Intelligence is a relative game, and while you are probably smarter than the average, there’s no shortage of people that could put you down as you so often do to others.

    Your sarcastic and arrogant style becomes quite monotonous after a short while.

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    • Two things are infinite: the universe and human stupidity; and I am not sure about the universe.
      – Einstein

      Hi John,

      Thank you for your constructive feedback. Aside from the obvious sarcasm in the above sentence, I think it was one of the Green tragedians who said “talk sense to a fool, and he calls you foolish.” Well, I think that probably applies perfectly well here, don’t you?

      If all I did was wrote a science lesson every day, you wouldn’t read it. You also wouldn’t have an emotional reaction to it because you would fail to understand that science isn’t enough of a basis alone to discredit the inappropriate, fraudulent and predatory behavior that makes up so much of the ASX healthcare landscape. I am sarcastic because in order to write many of these posts, I not only have to go up against the individuals that package up this bullshit and sell it to guys like you – but then I have to deal with guys like you who get all indignant because you were sucked in, most of the time because even simple, logical questions were not asked (like hmmmm… well, this company has spent $40m and now it is raising another $10m but in the last decade hasn’t actually produced anything… or why the “key science” of a company was published 23 years ago [discoverable from a 10 minute Google search] and yet the company is calling it new, game-changing technology).

      So often, I could write a 400 word post telling you why the science doesn’t make any sense, but most of the time it is the human behaviour combined with the science, where I find my contempt. And if you are such an extensive reader of my posts, then you would know that I regularly draw upon my own experiences, mistakes and weaknesses because they help me to identify them in others. I actually consider myself to be fairly average in intelligence, I am just willing to ask questions that you apparently aren’t. Unfortunately when one takes a critical position of “I am right, and you are wrong” this is often misconstrued for arrogance.

      I suppose my final comment for you “John”, is this is not HotCopper, where you can just anonymously abuse people, in turn creating enough of a herd mentality that you can discredit someone for having a valid opinion on the basis of their personality characteristics. If you want to criticise me personally, then identify yourself. I stand here transparently in front of you with my opinion and my identity. I get hundreds of abusive emails (and even anonymous letters) every week, abuse that I tolerate because it seems to be a necessary byproduct of taking a contrary viewpoint to the status quo.

      Frankly, if you don’t like what I write, then don’t come here and read it. I don’t foist it upon you.

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