Circulating Biomarkers: the Internet of Biology
Signals within the remarkable circulatory system
A few weeks ago learning about a new San Diego CA company called Cardea Biosciences they described a novel functionalized graphene biosensor with the tagline, ‘Powering the Internet of Biology’. This is a powerful metaphor – the Internet is seen as a ‘fourth Industrial Revolution’ that started in 1985 and going through the present per the MIT / Sloan School of Business in this interesting report "The seven technologies remaking the world". And as a metaphor, to get to true P4 medicine (a phrase coined by Lee Hood as ‘Predictive, Preventative, Personalized and Participatory) new sensor technology is needed, which I wrote up on the personal blog here.
The Internet of Biology
Taking a broader view of the Internet of Biology, you can view the circulation system in this fashion. Hormone signals operate at far distances from the pituitary gland. Creatinine and urea as waste products eliminated by the kidneys. And in the world of cancer diagnosis and treatment, circulating tumor cells are shed (and sometimes a CTC will take root as metastasis), serum blood proteins are present, exosomes are carrying bits of microRNA and protein cargo, and circulating tumor DNA and RNA are present as a by-product of necrosis or apoptosis.
The Internet of Biology, the circulation system, carries these signals and scientists for decades have worked relentlessly to identify them. Current protein-based biomarkers such as PSA for general prostate health, while in wide use and are inexpensive, suffer from high false-positive rates limiting its usefulness. About 15 years ago in the world of cancer research there was an explosion of discovery and characterization of the role of microRNAs and their association with cancer. And companies who manufactured reagents for microRNA detection looked seriously at using microRNAs as a tool for early detection, for example Exiqon (now a part of QIAGEN).
The practical use of circulating tumor DNA
For the past four or five years the use of circulating tumor DNA (ctDNA) has been in use for monitoring treatment and therapy choice. Large companies such as Foundation Medicine and Guardant Health, are joined by other companies such as Personal Genome Diagnostics, Natera, Sysmex Inostics and Inivata, to help realize the potential for ‘liquid biopsy’ for these applications.
In addition to monitoring recurrence of cancer or choosing therapy, analysis of ctDNA also is being examined by large pharmaceutical companies as companion diagnostics, to be used as part of large clinical trials now underway.
These are practical and useful uses of the powerful technology of circulating tumor DNA markers. Another application is current work underway for predicting immune-oncology therapy response (even with matched PD-1 or PD-L1 companion diagnostics, about 25% of patients receiving immunotherapy have durable responses) often are a combination of microsatellite instability (MSI-high) and tumor mutational burden (TMB).
The power of a network
In the past year or two there has been a resurgence of interest in using circulating tumor cells (CTCs) in conjunction with ctDNA as complementary approaches toward novel approaches in diagnosis and therapy choice of cancer, in addition to gaining greater understanding of cancer biology. The challenge of isolating and characterizing a single CTC in a background of literally a billion cells is a significant one. Nonetheless many companies continue to launch new approaches and new instrumentation to purify, enumerate, and genomically characterize CTCs.
This network effect of multiple approaches toward detecting cancer for characterization makes sense. The more ‘nodes’ on the network, the more valuable it becomes. (Metcalfe’s law can be applied to biology.)
Applied to Singlera’s approach toward methylation haplotype markers, the network effect applies here. We are examining literally 10’s of thousands of distinct CpG’s as methylation haplotype strings, and with these kinds of numbers as part of the network, any individual node dropping out has negligible effect on the detection of signal across the network.
Signal to noise – more data isn’t always better
There exists a danger to the thinking that more data is always better; it is not. Oftentimes with more data comes more noise. At a conference last year, one speaker who ran a prominent clinical NGS testing laboratory said emphatically, “I do not trust any circulating tumor DNA assay that claims to pick up anything less than 1%” in allele frequency. Even with unique molecular barcode technology, and other noise-reducing techniques as part of the informatic analysis, eliminating sequencing noise below 1% AF is a difficult problem.
More data – more sequencing depth – is not the answer. A better approach, to obtain better signal, is the answer. And here is where Singlera’s approach to bisulfite-treated cell-free DNA is so powerful. Even with a calculated six copies of target at 0.1% allele frequency, from 20 ng of input cell-free DNA, the conversion efficiency is so high that those CpG sites will be picked up.
In addition there are 10’s of thousands of them, an any individual stochastic drop-out will not affect the network signal as a whole. On top of that, since it is a targeted assay, the total amount of sequencing is parsimonious. Super-high depth is not required for detection.
Realizing the power of the internet of biology
Since about 1985 (per the MIT/Sloan Management Review) we are in the Information Revolution, where the ‘inflection point that marked the new revolution was the appearance of new technologies that fundamentally reshaped key aspects of the world’. Through the use of looking at new signals in the internet of biology, in particular methylation haplotypes, this may be an inflection point in the early detection of cancer.
The data is clear from the Taizhou Longitudinal Study and Singlera technology (access the PanSeer whitepaper PDF here) that cancer can be detected four years before conventional diagnosis through the power of the internet of biology, looking at a signal devoid of noise. Intrigued? Contact us for more details or to look into collaboration or partnership opportunities.