This story has been updated to include comments from the Wyoming Public Health Laboratory.
NEW YORK – With a rapid, automated solution that incorporates Oxford Nanopore sequencing for diagnostics and surveillance, Clear Labs is growing its footprint in both applied and clinical markets.
The San Carlos, California-based firm garnered $60 million in Series C financing in May, and last week the firm presented its SARS-CoV-2 next-generation sequencing system at the World Microbe Forum, presenting initial data on surveillance for clinical and wastewater samples.
Initially focused on food testing and applied markets, Clear Labs had always planned to expand into other domains as well, CEO and founder Sasan Amini said in an interview following his presentation.
Clear Labs manufactures a system called Clear Safety for the applied space. Motivated by the coronavirus pandemic, however, and with $18 million in strategic funding, the firm developed its first clinical application and obtained Emergency Use Authorization from the US Food and Drug Administration last year for a SARS-CoV-2 test and diagnostic system called Clear Dx.
The EUA SARS-CoV-2 test on the Clear Dx system enables labs to run both EUA diagnostic tests and genomic surveillance assays simultaneously.
Clear Labs is currently the only manufacturer of a fully automated, fully integrated platform for DNA sequencing that uses robotics and cloud-based analytics, according to Amini.
"The key value that we deliver to our customers is accelerated outcomes with improved accuracy" compared to standard sequencing workflows, he said.
Specifically, the Clear Labs system performs automated library preparation, followed by an automated Oxford Nanopore GridIon whole-genome sequencing workflow, and then delivers reports to users through cloud-based software.
The process requires about 30 minutes of hands-on time, Amini said, with a total turnaround time of less than 24 hours.
In his World Microbe Forum presentation, Amini noted that Clear Labs has had one new customer per week since launching Clear Dx in September.
Publicly disclosed end users include the Nevada Public Health Laboratory, which used the system to detect the first local occurrence of the SARS-CoV-2 alpha variant, formerly known as B.1.1.7, in January. And the Medical University of Nebraska used Clear Dx for early detection of viral variants in the state, for example finding the first local cases of the iota variant.
The Wyoming Department of Health was also an early adopter of Clear Dx, and has been using the system for surveillance since January. The lab used the Clear Labs instrumentation to detect the first case of the delta variant in the state, with a total time from sampling to testing to NGS of six days, and this week the state passed the 10,000 mark for sequencing viral genomes, sequencing more than 15 percent of all positive cases in Wyoming.
"Wyoming is now ranked number one in the US for the percentage of SARS-CoV-2 positive samples that they sequence," Amini said, referring to data from the US Centers for Disease Control and Prevention. This is due in part to the ease of use of the Clear Labs system, he said.
Indeed, Amini asserted that the US states with the fastest times from positive sample to depositing results in GISAID are Clear Lab users. "For example, in Nebraska the mean time to sample to deposit into GISAID is only five days," he said.
Cari Roark Sloma, the Director of Wyoming Public Health Laboratory, said in an email that the lab began using the Clear Dx system for surveillance purposes in December. The WPHL relies on Illumina and Oxford Nanopore platforms as well, she said, and the availability of reagents, turn around time, and workflow dictate which platform is used.
Sloma noted that the advantages of Clear Dx include that it is reliable, quicker than the Illumina platforms, and "very hands-off," allowing staff to do other work while it is running.
Some offsetting considerations include the cost of the reagents and consumables, Sloma said, as well as sensitivity issues she said are inherent to Oxford Nanopore technology. For Ct values greater than 25 and samples of unknown Ct value, the lab uses Illumina platforms.
Nevertheless, Sloma highlighted that the lab was able to sequence as many as 224 specimens in one week on the Clear Dx.
"It's a real workhorse," she said, adding that Clear Labs has also been able to provide the lab with "a steady, reliable supply of reagents, and they offer exceptional customer service."
Current use cases, future plans
Typically, whole-genome sequencing requires users to run batches of samples in order to bring the cost to process each sample down. The workflow also typically requires intensive hands-on time and expertise to perform correctly.
"What Clear Labs really does is to make batch sizes so practical that people can start processing samples in real time, and that really unleashes the power of genome sequencing technology," Amini said.
Clear Labs recently developed a prototype "near real time" variant monitoring engine for its system, which Amini presented to the microbiologists in attendance at WMF.
The engine flags genomes of variants of concern in all the cloud-connected instruments, which he said can be used to determine local prevalence as well as for what he called predictive monitoring.
As an example, Clear Labs used retrospective data to show that the variant monitoring engine could have flagged the alpha variant as a variant of concern when it was present at a prevalence of approximately 6 percent, a result achieved simply by pulling forward the overall sequencing timeline. Instead, by the time the alpha variant had been sequenced and linked a rise in cases, it already represented half of the cases in the UK, Amini said.
At WMF, Amini also presented pilot wastewater-based epidemiology data using Clear Dx WGS.
The pilot WBE study examined 12 wastewater samples and detected as few as 5 copies of virus per milliliter of sample. Amini said in the presentation that high viral load in samples also enabled variant lineage detection.
Surveilling for variants may become trickier in the future if infection after vaccination results in no symptoms, and the WBE approach has an advantage of detecting viral sequence shed by asymptomatic people, Amini noted.
Although Clear Labs is pivoting to emphasize the surveillance capabilities of its system, it will maintain its position in applied testing as well, Amini said.
Interestingly, he noted that some of the constraints inherent to sequencing can be even more impactful in applied markets, so entering the molecular testing market through the food space served as a crucible of sorts.
Like the rest of the microbiology lab universe, food testing has a shortage of highly trained technicians. "Many of the food operators don't necessarily have degrees in molecular biology, or biochemistry, or genetics, so the solution needs to be very easy and fully automated for them."
Furthermore, "Food applications are more time-sensitive, because food is perishable, and they are more price sensitive because food is a low-margin business," Amini said.
For this space, Amini said another important component is physical redundancy of hardware in the instrument, so that if one of the units fails there is a backup.
Oxford Nanopore was a better fit for these reasons compared to other options "because it was faster, had cheaper options for lower throughput sequencing cases that we are interested in, it provided the physical redundancy needed, and it could be fully automated," Amini said.
The system currently uses Oxford Nanopore GridIon sequencing under a distribution agreement signed in 2019. And, "We work closely with them to make sure that our end customers have the best customers experience," Amini said.
He suggested that Clear Labs' application is complimentary to Oxford's core strategies, since other users, as well as Oxford itself, tend to emphasize the system's point-of-care applications for research and clinical use.
"They created a system that is portable and takes advantage of long-reads, but what we tried to do is take advantage of the time to results and cost benefits for low-throughput applications," he said.
That said, Amini began his career as a molecular biologist and researcher at Illumina, and suggested that the goals of Clear Labs go beyond any single platform.
"The cost of sequencing has dropped faster than Moore's Law predicted, and I anticipate sequencing will continue to create new and emerging markets," Amini said. "It is definitely the time to start making it so simple, reproducible, cost effective, and rapid, so anyone can walk up to a system, spend a few minutes to load it, and get the results back the same day," he added.
Currently, the firm markets Salmonella and Listeria surveillance assays to the applied space.
Amini noted that Salmonella has more than 2,400 serotypes, not all of which impact human health, so strain information can be quite useful. And, information about Listeria pathogen sequences can help in surveillance, since a chronic, or resident Listeria infection with the same strain suggests mitigation efforts are failing, while detection of a new strain would indicate the pathogen has just arrived in raw materials or on an employee.
One food manufacturer that is a Clear Labs customer, for example, had a resident Listeria infection in its plant it was unable to squash over many years, Amini said. Using PCR-based testing, the manufacturer had assumed it had one source for its problem, but, "The moment they went live with our system, they saw that they were actually dealing with five independent Listeria strains," Amini said, implying five different sources of contamination.
"For food companies, the descriptive layer added to the diagnostic can become very powerful," Amini noted.
That said, Clear Labs also strives to deliver sequencing data in a way that is actionable, with clear insights, such as "which variant am I dealing with, or have I seen this same pathogen in the past," he said.
The firm now plans to dedicate its Series C funding to broaden the availability of its existing test menu but also introduce new tests, Amini said. These will include lab tests as well as additional analytics aimed at the needs of current customers, a group that now includes public health laboratories with installed instruments.
In terms of SARS-CoV-2, because vaccination is now helping contain the number of positive cases, a higher percentage of them could now be sequenced, to better surveil viral evolution and get advanced warning on any variants that might escape vaccines, Amini said.
"We have spent billions of dollars on vaccinating the US to hopefully reopen the economy — we just cannot afford to go back," he said.