Human genome sequencing has sure come a long way, baby. The Human Genome Project, started way back in 1990, took 13 years to sequence the first human genome and cost a hefty $3 billion. Fast forward to today, and that same process can be performed in 24 hours and costs less than $1000.
But when it comes to hot-button ethical issues, they don’t come much hotter than the ethics of DNA sequencing. The subject quickly brings to mind uneasy visions of dystopian futures (think Gattaca) where the value of human life is reduced to the value of its DNA, where ‘geonism’, or discrimination based on genetic predisposition, is the norm.
That, however, is hardly the full picture when it comes to the perils and potential of Next-Gen Sequencing (NGS). Because on the other side of that problematic coin is the ability of Next Generation Sequencers to diagnose life threatening illnesses hyper-accurately and on a massive scale, allowing early intervention and treatment of otherwise intractable illnesses.
That’s the space which New Zealand biotech company Caldera Health is currently exploring, identifying biomarkers and developing sophisticated software diagnostic tools for revealing prostate cancers in men. The company is using Next-Gen Sequencing to identify and measure multiple different genetic markers that occur in prostate cancers, enabling medical staff to make more informed diagnoses and better decisions around treatment options.
Current prostate cancer tests, such as PSA blood-test, generates large numbers of false positives and missed diagnoses, and doesn’t distinguish between aggressive cancers and benign strains of the disease – leading to unnecessary prostatectomies. Both original founders of Caldera, Jim Watson and Richard Forster, were missed by then-current screening technology and ended up with metastatic cancer. In 2012 the US Preventive Services Task Force recommended against mass PSA screening for these very reasons.
Image: Keith Hudson, director of research and development, Caldera.
“Across the OECD there are over 100,000,000 PSA tests,” says Keith Hudson, director of research and development, Caldera health.
“There’s a lot of testing that goes on and it’s just not very accurate.”
Caldera is hoping to create an alternative test which can identify prosate cancer by gauging the underlying genetic changes in the cell.
“We’re trying to develop accurate, biopsy-based gene tests. We’ll take a biopsy of the tissue and do genetic tests on it, but that’s just the first stage, using biopsy tissue. What we really want to do is develop a non-invasive test. Urine is very closely associated with the prostate and we believe we’ll be able to develop a non-invasive, high through-put test. In the future we’d also like to develop a prognostic test so we can say ‘this is what’s going to happen to you with this cancer and how it should be best treated’.”
To do that, the company is developing ‘RBAS’ technology (or RNA biomarker amplicon sequencing), where the company isolates RNA from a prostate biopsy sample, selectively amplifies some of those RNAs and then uses a next-generation sequencing device to count the number of molecules there, which can be indicative of the changes caused by the cancer.
Ultimately, the company hopes to develop a way to identify the ‘signature’ of cancer in those cells, enabling a large scale and low cost screening system that will be far more accurate than the current technology.
“This is called a targeted gene expression approach and we’ve got a patent around this method. Currently it’s a manual process but we are moving to automation that will have that scale, it will be low-cost and it will be accurate.”
Being able to offer accurate, cost-effective and quick diagnostic tests comes at a price, however. As the technology evolves, so too does the need to be able to process the vast amounts of information generated in the process. NGS is rapidly becoming one of the biggest of the big data challenges.
“We use next generation sequencing and we combine that with customised analytical software to generate our results,” says Hudson.
Caldera is using statistical approaches (statistician Dr Dug Yeo Han is a recent addition to the team) and is working with Challaghan Innovation to do an exhaustive search of the 200 billion possible combinations of the relevant genes, a process which involves sophisticated algorithms and supercomputing capacity.
“With first and second generation sequencing you were able to perform analyses of individual sequences as they were generated,” says Caldera chief scientist, Dr Kristen Chalmet, “now there’s simply too much data to do that. We had to develop customised bioinformatic tools that would allow us to deal with massive amounts of data and to present the results in ways that would be clinically useful.
“With NGS, the sequencing itself is no longer the main challenge. How you handle the data afterwards is at least as demanding. We’re generating so much data that the traditional cloud is not sufficient for our storage purposes. We’ve had to find more cost effective ways of transmitting our data and backing it up. And we’ve developed tools that allow us to process it, on demand, in the cloud.”
Though the challenges are great, the company is confident that they will have a viable product within the next few years.
Image: Graham Watt, managing director, Caldera
“Caldera has been pretty much under the radar until now,” says managing director, Graham Watt. “But you can see, given the disease we’re trying to address and the way we’re trying to address it, there’s a huge social good to the project, but with a huge medical and commercial opportunity.”
“It’s possible that we could have a product ready by 2017. It’s not a ten year time frame, because much of the work’s been done. We’re not talking about a blue sky thing here.”
The company is currently engaged in Series E funding and has raised $1.2 million of a $2 million funding goal.
