BALTIMORE – Having secured an additional $13 million equity investment from Hitachi High-Technologies earlier this month, genome analysis technology company Nabsys plans to take another crack at the whole-genome mapping market, this time focusing on the human genome.
The Providence, Rhode Island-based firm said the additional funding from Hitachi High-Tech was triggered by "a technical milestone," which increased the throughput of its high-definition genome mapping technology — coined HD-Mapping — more than 10 times.
With this advancement, Nabsys said it is now poised to offer a new platform for human whole-genome mapping through an early-access program in the first half of 2023, followed by a full commercial launch soon after that.
Originally established in 2005, Nabsys has encountered some hiccups to get this far. The company initially tried to develop and commercialize a platform for single-molecule DNA mapping, based on a solid-state nanodetector technology devised by researchers at Brown University.
However, a management shakeup in 2014 steered the firm off the genome mapping track to focus on cancer genome analysis, which turned out to be an unsuccessful approach and ultimately led Nabsys to close its doors. After a six-month hiatus, the company reemerged with a financial restructuring in 2015, bringing back some of its original leadership team while reclaiming the company’s genome mapping mission. In 2017, Nabsys announced plans to commercialize an instrument the following year, focusing on microbial genome analysis, but the full launch did not quite come to fruition.
In 2019, Nabsys brought in Hitachi High-Tech as an investor, receiving $21 million of equity investment to bolster its balance sheet. With the investment, the company has since released about 30 instruments for microbial genome mapping, according to Nabsys Founder and CEO Barrett Bready. In April of this year, the company received $25 million in another funding round from Hitachi High-Tech, which eventually expanded to $38 million after the most recent addition of $13 million.
Despite the company's previous attempt to commercialize its electronic genome mapping technology mostly for microbial applications, this time Nabsys is pivoting to human genome analysis. "As a company now, we are really focused mostly on human applications," said Bready. "Now we have the throughput to really do those applications."
At its core, Nabsys’ HD-Mapping technology is a semiconductor-based, electronic whole-genome mapping approach supported by nanodetectors. "Some people have likened it to kind of a combination of optical mapping and nanopore sequencing," Bready said, adding that while the company’s technology in the early years stemmed from Brown University, HD-Mapping was completely developed by Nabsys in house.
The HD-Mapping workflow typically starts with high molecular weight DNA isolation, for which the company recommends a commercial kit that can extract DNA between 50 kb and 200 kb in length. After that, DNA molecules are labeled by nickases — restriction enzymes introducing single-strand cuts on the DNA — at known recognition sites at a recommended average interval of around 4 kb. The tagged DNA is then coated with modified RecA protein, which can help boost the signal-to-noise ratio and improve measurement accuracy downstream.
As the analyte electrophoretically translocates through the solid-state nanochannels at high velocity — currently at a million bases per second, according to Bready — voltage signals are measured by the nanodetectors, indicating the distance between sequence-specific motifs on the DNA and the shape of the molecules.
Despite their conceptual similarities, Bready said a major difference between the company’s nanodetectors and conventional nanopores is that the former produces a voltage measurement as opposed to a current signal typically generated in nanopore sequencing. "The big advantage of this is, you don't suffer from crosstalk when you have a lot of them close together as you would with nanopores," he pointed out.
Meanwhile, because electronic genome mapping eliminates the optical component, it has potential advantages over optical mapping in terms of higher resolution and "more degrees of freedom" when choosing recognition sequences and densities, Bready said. The company currently says the technology can detect structural variants from about 300 bp in size up to large chromosomal rearrangements.
More importantly, Bready claimed electronic mapping can tackle DNA molecules that are shorter than those required for optical mapping. "Optical mapping usually disregards all the reads below 150 kb," he said. "[With electronic mapping], you are able to use molecules much shorter than that."
Once a sample is loaded onto the instrument, the signal can be generated within seconds and processed in real time, Bready said. Additionally, in collaboration with Hitachi High-Tech, Nabsys developed software called Human Chromosome Explorer, a Google Cloud-based whole-genome assembly and structural variation (SV) analysis pipeline to help customers navigate the results. With the software, "even if a lab doesn't have large computational biology capabilities, they can still do these analyses," he said.
According to Bready, the current turnaround time for the HD-Mapping workflow, from sample isolation to variant calling, is between 50 and 55 hours, which is split between sample preparation and data collection.
As of now, the HD-Mapping platform can process one chip at a time, which contains 256 nanochannels, Bready said. While each chip can typically accommodate one sample, it can also be reused depending on how much it has been used during each experiment.
Bready said the company plans to continue to scale its technology. "We are at the very beginning of our scaling ability," he said, noting that a future iteration of the platform will increase the throughput by "several more orders of magnitude" while boosting its multiplex capabilities to be able to accommodate multiple samples at a time.
In terms of cost, Bready said the elimination of optical components gives the company’s technology a competitive edge over optical mapping, both regarding the instrument and consumables. Nabsys’ HD-Mapping platform, which has a size similar to a desktop computer, is currently priced at under $100,000. Consumables costs for a high-coverage human genome are about $300, which is dominated by the chip cost. As Nabsys continues to scale the technology, costs per experiment will go down, Bready added.
Despite these promises, without much data, it remains to be seen how the new platform will perform in customers’ hands. Nabsys will also face competition from established players like Bionano Genomics, an optical genome mapping company that has created some buzz in the field of cytogenetics, has many peer-reviewed publications and a sizable customer base and has made significant headway in driving the clinical adoption of its technology.
Bready said competitors’ progress in building recognition for genome mapping technology is in fact beneficial to Nabsys. "I think everything that they are doing is ultimately good," he said. "It's developing the market."
With the additional funding from Hitachi High-Tech, Bready said the company is preparing to kick off the early-access program for its new HD-Mapping platform in the first half of 2023 while preparing for the technology’s full commercial launch soon after that.
"We finally hired some non-R&D folks," Bready said, adding that the company, which currently has 20 employees, plans to substantially grow its workforce over the next 24 months to build up its commercial team.
Having displayed the new instrument at this year’s American Society of Human Genetics annual meeting last month, Bready said many researchers have already expressed an interest in becoming early customers. Nabsys has yet to finalize its list of early-access partners, though, with whom it will collaborate to produce benchmarking data for the technology.
Regarding intellectual property, Bready said the company currently has 17 patent families internationally covering its core detection technology. He also said that Hitachi High-Tech, though it has a minority stake in the company right now and is a great strategic partner, does not have a royalty agreement with Nabsys and does not own any of the company’s IP.