Friday, June 07, 2024

CariGenetics: Breakthrough Breast Cancer Genetics in the Caribbean - but Also a Template for ONT Clinical Push?

London Calling isn't nearly as exhausting as AGBT, but the first day of talks is packed and then follows with the social event that goes late - this year with CEO Gordon Sanghera living out his dream of being the frontman for a band.  Then if you'd like you can follow the crowd to a pub to drink on ONT's tab (that and crashing the ONT wrap-up dinner is the extent of my drawing personal benefit from ONT, contrary to a commenter on the prior piece who wrongfully believes they fund my LC expenses), and when that pub closes to another one (I peeled off after the first pub).  So one can be a bit draggy heading into the second morning, but that was solved quickly by CariGenetics CEO Dr. Carika Weldon, who wowed with an exuberant strut down the central runway to a lively calypso beat - and then wowed everyone further with a stellar presentation.  She also gave the lunchtime Product Demo talk (alas, I can't find that talk either on YouTube or in Nanopore Community) in the central product area, filling in some colorful details on her young company's early travails - all resolutely conquered.

CariGenetics CEO Dr. Carika Weldon presenting on the main stage at London Calling 2024


Dr. Weldon reviewed the multi-pronged CariGenetics value proposition in her presentation - you can watch it yourself on YouTube.  The Caribbean, with her home island of Bermuda ('it is not a triangle!" she declared) culturally if not strictly geographically included, has a highly admixed population due to the complex (and often unpleasant) history of how these islands were peopled.  African ancestry dominates, but essentially all other population groups have contributed.  These twenty-six island nations also have small populations individually - as she bluntly put it, "we tend to date our cousins" - but together over 40 million individuals.  Economic development levels vary widely; some islands are relatively wealthy but some display extreme poverty (or saddest of all, the current state of violent anarchy in Haiti).  Many have socialized medicine systems. 

And the islands have high incidence of breast cancer; as high as 30%.  Barbados has one of the highest breast cancer death rates in the world, despite having a highly organized socialized medicine system. This tracks a general trend of Black women suffering higher rates of breast cancer and higher mortality.  Current testing involves shipping samples to the US for testing, which is both slow (up to 16 weeks!!) and expensive - and the reference databases used reflect very different populations and alleles than may be found on the islands.  These panels primarily focus on BRCA1 and BRCA2 for testing; could other loci be important in Caribbean populations?  Indeed, prior studies showed that BRCA1+2 testing might miss as much as 13% of inherited breast cancer in the Caribbean.

So CariGenetics' model is very attractive.  Indeed, providing virtual breast cancer panels via computational filtering of whole genome data proved faster and cheaper than the US-based testing services.  Indigenous molecular testing capability is built.  CariGenetics' study has also already identified new deleterious alleles in breast-cancer related tumor suppressors, and has started identifying distinctive structural variants in island populations.  As part of the ethics approval for the study only a pre-defined panel of cancer-related genes were reported on - but this proved very valuable as large numbers of mutations showed up in non-BRCA genes such as mismatch repair genes.  The yield of deleterious alleles in the breast cancer subject samples was often much higher than would be estimated from prior (non-long read) studies - it was expected to find mutations in 1.3% of subjects (basically, in at best 1 patient among the 51 sequenced) and instead about 1/5th of subjects (10/51) had a deleterious mutation in a virtual panel gene - and only 4 of those individuals had BRCA1/2 mutations!   Many of those other genes suggest therapeutic avenues that might not be routinely considered in the context of breast cancer; this study is opening up new options for patients.  Dr. Weldon also noted that large pharmaceutical companies are showing interest in the results and are discussing further studies in the region. 

As suggested above, CariGenetics did experience a bit of perils-of-Pauline in booting up.  As pioneers in this space, the ethics approval drew out to 14 months, apparently over concerns around ancillary findings and their potential to disrupt the healthcare system.  A university computer system they were planning to use was attacked by foreign hackers.  No fast internet connection existed to upload to the cloud from CariGenetics's laboratory site, so Dr. Weldon drove hard disks to the university in her car.  Logistics of obtaining consumables weren't always easy - Bermuda's position in the Atlantic leads to more flights going over it than to it.  Still, her remark that getting fresh batches of reagents  took two weeks points to ONT's ongoing failure to treat consumable distribution as a pressing issue.  Nobody can sequencing anything anywhere if they can't get flowcells and kits!!!

Most of CariGenetics' findings have been confirmed by short read sequencing - but many of those remaining are structural variants which short read sequencing just isn't sensitive to even if you know exactly what you are looking for.  As Dr. Weldon noted, the long read data in these cases is unequivocal - but how to convince a short-read focused establishment?

CariGenetics in A Box?

An interesting question arises: to what degree could the CariGenetics model be replicated in other areas?  At one extreme, one might think that the incumbent cancer test companies are vulnerable to undercutting on cost.  At the other, perhaps only a subset of nations are sufficiently stable and wealthy to provide a favorable environment for CariGenetics clones, and perhaps in many countries the regulatory barriers will be troublesome.  It would seem that generating refined estimates of this potential would be a highly valuable activity for ONT - as well as figuring out how to act on it.  Are there technical developments which would help ease the booting up of such companies?  Should ONT be looking for interested local investors and interested local scientists and perhaps sometimes playing matchmaker between them?  

Many issues would arise.  For example, a substantial part of the bioinformatics for this study was performed by Dr. Miten Jain, and cloning him is probably not a feasible solution.  Some of the computation used Geneyx's informatics pipelinenull, which is aiming to provide clinical reports - that might be a practical approach.  CariGenetics used a private cloud in Bermuda for data storage; can this solution work everywhere. The logistics issue would also loom large: ONT would have to truly knuckle down and figure out how to ship product to a diverse set of jurisdictions across the world.  

Not a trivial problem, but a focused small team in a week could certainly come up with multi-factor ranking of every country in the world on such aspects as availability of air courier services, national healthcare system, corruption index, regulatory environment, and so forth, while another team tried re-thinking the logistics system from the ground up.  Yet another team would do a gap analysis on the informatics.  Those initial brainstorming / idea hackathons could be followed with focused efforts to vet the details (and perhaps often kill ideas!) of the most promising options.  It's not the sort of projects that yield gaudy slides for London Calling; this sort of scut work has never seemed to be prioritized at ONT.  But it would be the work that would identify if multiple opportunities exist around the globe.

That's not a trivial amount of work - but if Oxford Nanopore is truly committed a product company and not just a generator of technology demonstrations, they must get serious about being serious.  Making a real impact in the medical world requires solving all of the steps between patient and answer, not just the patient sample to FASTQ portion.  Grand visions are inspiring, but real progress requires solving all the boring bits and bobs.

1 comment:

Nicolas said...

You're featured on the video of the talk, Keith!