We may still be five Years out until We Can Sequence Everyone
I had the chance to attend the Precision Medicine World Conference PMWC 2023 SV in the last couple of days. Some 2,000+ individuals from across the life sciences and healthcare sector – academic and pharma researchers, physicians, innovative tech companies, investors, regulators, and payers – attended this highly informative scientific gathering. While there were five tracks that covered various different aspects of precision medicine, including AI and data sciences, early oncology applications, advancements in gene and cell therapies, real-world data applications, clinical utility of liquid biopsy, populations scale omics, among others, in this post I wanted to focus on one particular panel discussion that had recently gotten a lot of attention: “How Will Cheap Genome Sequencing Impact Genomic Medicine”, as the “$200 genome” is at the top of everyone’s mind these days.
Euan Ashley (Associate Dean and Professor of Medicine and Genetics at Stanford University) was moderating the lively discussion, which included Aleks Rajkovic (Chief Genomics Officer, UCSF), Shawn Levy (SVP Applications and Scientific Affairs, Element Biosciences), David Bentley (Vice President & Chief Scientist, Illumina and also the recipient of this year’s PMWC Pioneer Award), Stacey Gabriel (Chief Genomics Officer, Broad Inst.), and Sean Hoffher (Chief Operating Officer and Clinical Director, Fabric Genomics).
Some quotes to highlight:
Aleks Rajkovic:
- “Let’s be clear, the cost of a genome is not $100 or $200, it requires a lot more. It is currently more like $1,000 for healthcare organizations. I believe other disruptions are needed.”
- “We should push our healthcare system to go for the whole population. Medicine in the US has a lot of inequities.”
- “Genomes should be part of standard of care.”
- “Insurances want you to be more specific. The number does not matter, it is not about the cost. You have to show to them that it is cost-saving, or show that it is improving the quality of life.”
Shawn Levy:
- “As a consumer I want a different genome than if I am a cancer patient.”
- “If we focus on the low-cost sector it allows us to look at the other barriers.”
Stacey Gabriel: “We can get them all or we get one of each (when speaking about the different platforms). The more important question though is, what is the moment a platform comes into production?”
Bentley:
- ” Even though you could get an even cheaper genome, you really want an accurate and good genome. We are not about cheap; we are about good and affordable.”
- “Cost is coming down and that changes what is affordable. We have to bring the practicality and affordability together with scale.”
Following is my summary of interesting key points discussed by this well assembled panel.
What is cheap genome sequencing: how much does it cost today and what should it be ideally cost and why?
Rajkovic: Cheap sequencing will improve diagnostics as it will reach a wider group. But let’s be clear, the cost of a genome is not $100 or $200, it requires a lot more. It is currently more like $1,000 for healthcare organizations. I believe other disruptions are needed.
Levy: From a medical genome perspective, genomes are already cheap, but the $200 genome recently announced by Element is the goal, it is an idealized state. It does not include the cost of the machine, and if included and running about 1,500 samples per year, the cost would be closer to $400 per genome.
Bentley: For years we have been asked – by the British prime minister and Genome UK – to reach the $1,000 genome loaded in with other costs. This is now history, as now we are able to do the $200 genome with the new machine. I think it is cheap today even when loading in the other aspects. Even though you could get an even cheaper genome, you really want an accurate and good genome. We are not about cheap; we are about good and affordable. Now healthcare starts to see that price point, and it fits that price point.
Gabriel: The way we look at cheap is when sequencing is about $1 per Gigabyte. But really when running whole centers, I have to think beyond that number and include overhead cost. With the new sequencer: a research genome costs about $300 for a 30x genome, the clinical genome (at the same depth) will most probably cost more like 2-3 times more.
Hoffher: The last six months brought awesome news and driving the cost down is truly good. At this point we have to think about post data processing and data interpretation. Our focus, right now, is to drive the interpretation price down, like to $200 per genome. We take an augmentation support approach, as the human is not out of the equation. We leverage the tool by drilling down on the variants of interest.
Gabriel: We really need more data so we can deliver the next cheapest genome, that includes the interpretation component.
Rajkovic: I am very optimistic and ideally we have a point of care instrument in all organizations. But we still need to have someone to sign it out into a report to make sure that it all makes sense. If you can get rid of a lot of informatics steps that can be automated, then you can look at all the genome has to offer.
What are the benefits the new technologies can bring?
Levy: Over the years I have worked with all the various platforms at the HudsonAlpha Genomic Services Lab (GSL) (now HudsonAlpha Discovery). We now have a great opportunity to introduce change based on the learnings – competition is a good thing as we see a renaissance of the industry. Diversification is good and makes us all feel better. Element’s design is not just with sequencing in mind, but also thinks multi-omics.
Bentley: We applaud new contenders. We agree competition is good. Early on in the sector there was a lot of competition in the short read sector. After that initial competition faded (with acquisitions, etc.), and we at Illumina felt lonely at times. It allowed us to focus on all the technical elements, as well as improving the chemistry and enzymatic aspect to bring the cost down.
How do you feel about the new techs and how do you think about them?
Gabriel: Over the years, we had tremendous partnerships. We, as an NIH-funded genome center, had a chance to try out the various different technologies on the market. We have been doing a lot of benchmarking, but for a long time we had not much to do when we were only using Illumina. Now with all of those platforms, be it Element Biosciences, Singular Genomics, Ultima Genomics, or PacBio there is the notion of cheap, but there is the world of cancer diagnosis as well.
How do you balance a portfolio as a genome center?
Gabriel: We can get them all or we get one of each. The more important question though is, what is the moment a platform comes into production? For me, this is the more relevant question and Illumina set a high bar of qualifying for production.
Do you see the world in short and long reads?
Gabriel: I think there is a nice way of symbiosis, but it all depends on the specific application needed. It is not an OR, it is rather an AND.
Where do you see these new technologies being more available in the (near) future?
Rajkovic: For me genomes should be part of standard of care. Preconception screening is very important, as well as sequencing smaller and smaller cells accurately in the pediatric and prenatal sectors. The prenatal sector is very important when it comes to bad disease prevention. Today the biggest consumer of sequencing is cancer and most probably pediatric care. 70% of all diseases are new diseases. But we also need to get reimbursement in place for these screenings. While we should do prenatal sequencing, we should also extract more data for genomics, do screening in cardiology, and other clinics. They all would benefit from more testing.
On the clinical side, where would these new technologies have a significant impact, and where would you deploy them next?
Hoffher: We want to focus on whole genomes and once cheaper, then we will be able to replace panels. Screening in pediatric care is already there for some, and prenatal screening has huge potentials but it is tough, especially when it comes to handling and processing the sample types. There is a gap in the prenatal sector. We certainly see a lot of interest in the genome.
Levy: We are glancing over the ethics question. As a consumer I want a different genome than if I am a cancer patient. If we focus on the low-cost sector it allows us to look at the other barriers. Low-cost genomes will not quickly turn into reality.
Bentley: If the cost is now longer a big issue, the things that come onto the table is a non-disruptive workflow! It should not take 3 days to do a genome. At the end it will not be a genome, it is rather just a test with high quality data as the output.
Rajkovic: With the cost of a genome being low, more people will get sequenced, but you will also find inequity. We should push our healthcare system to go for the whole population. Medicine in the US has a lot of inequities.
Levy: One point of equity is your most homogenous population and in the US that means getting all newborns sequenced, but the logistics is huge.
Gabriel: We can take COVID as an example: we sold $15 COVID PCR tests and we ended up doing 38M tests – so much more was done because it was cheap, but the logistic nightmare started. Of course, PCR testing is a lot easier but it was still a nightmare and we can learn from it.
How low does it need to go for the insurance companies to pay?
Rajkovic: Insurance companies look at exomes and genomes as research. Insurance companies want you to be more specific. The number does not matter, it is not about the cost. You have to show to them that it is cost-saving, or show that it is improving the quality of life. The US healthcare system does not work that way. Illumina has done a lot to clear the regulatory side.
Bentley: Cost is coming down and that changes what is affordable. We have to bring the practicality and affordability together with scale. This is different in the UK.
David Ledbetter (Geisinger) – a comment from the audience: You have to show evidence of clinical utility. This is required to convince insurance companies to pay. The other aspect to consider is the physician barrier: genetic testing is too complicated for them. And then there is also the turnaround time issue.
Levy: Genomes work on the collective evidence.
Ashley: Multi-institutional studies are important.
When can we expect a cheap and accurate genome all when?
Rajkovic: I think the genome is cheap enough now. Available now if you want to pay for it. But it will take five years for everyone.
Levy: Five years.
Bentley: Five years.
Gabriel: Look at the All of Us Research Program to get a free genome sequenced. Otherwise, my answer is five to ten years.
Hoffher: I predict one to three years, but it will require moving to other bottlenecks.
