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Startup SimplSeq Aims to Shake Up Sequencing Sample Prep with Easy, Fast Tech

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NEW YORK – A small startup called SimplSeq thinks its technology is going to revolutionize sequencing sample prep and ultimately usurp the behemoths in the field.

A spinout of a new tech incubator called Murrieta Genomics, the firm is now beta testing a technology that it claims is faster and simpler than standard methods, and can enable better use of precious liquid biopsy sample material.

Brandon Young is the founder and CEO of SimplSeq, as well as the inventor of the patented core technology. The method he developed replaces DNA and RNA purification, includes a library prep method, and takes six hours to run.

The method works in part by attaching the 3' end of DNA to solid supports, Young said in an interview.

These can be beads or plates, but either way, the approach obviates the use of the electrostatic interactions common to standard column- or bead-based products. Standard methods typically rely on binding the negative charge in the backbone of nucleic acids, but since negatively charged molecules abound, they can be non-specific, Young said. They also seed biases in processing that get amplified during the workflow because they favor longer strands of DNA with a higher charge density.

In contrast, the SimplSeq method, "enables us to go in and specifically target the DNA molecule," Young said.

Once nucleic acids are either covalently or affinity-bound to the solid substrate, they can be made single stranded. "When you start operating in a single-stranded world, the complications you have in sample prep, especially in targeted sequencing, really become minimized," Young said.

For example, most next-generation sequencing library preparation workflows require ligation, PCR, targeted capture, and a second PCR step. "Each of those steps introduce bias and they are not 100 percent efficient," Young said. The SimplSeq method "skips those by doing what is the equivalent of cDNA synthesis," he said.

Besides being faster, the new technology differs in other ways as well, Young said. Current technologies have issues with the on-target rate, uniformity of melting temperatures of different probes, and impacts of temperatures changes that occur during wash steps. The SimplSeq skips the targeted capture, he said, because the single-stranded nature of the workflow essentially turns the process into reverse transcription using specific primers. "Once you put those in, that becomes your first strand of cDNA and you can pull those off while your initial DNA or RNA remains bound," he said.

As if mimeographed, the genomic sample can then be used repeatedly as a template, such that a precious sample is not used up in the sample prep workflow.

SimplSeq is currently researching just how long a sample can be maintained this way, but so far has seen a stability time of four weeks. The firm is now testing out covalent chemistries that are less fussy about temperature changes to try and push the storage limit.

In addition to long-term preservation, the method could be useful so that labs can go back to a sample and look for new markers if needed, or to share copies of rare samples.

"You can replicate sample that is bound and send out a daughter copy to various groups without using up input sample," Young said.

And, unlike copying genomic material by passaging it in cultured cells, this method "maintains a faithful copy, using enzymes that are as accurate if not more accurate" than ones in immortalized cells, and it can take hours instead of days to do, Young said.

This aspect of the technology could be useful for liquid biopsy research and testing, where patient samples are rare and in high demand.

SimplSeq is now sending its kits out to collaborators to get user impressions and data.

But even at this early stage, Young said he believes other companies in the space should pay attention because this technology will ultimately take their business away.

Competing technologies come from Thermo Fisher Scientific, Illumina, and Qiagen, as well as Agilent Technologies, Twist Bioscience, and IDT on the assay side, he said.

Overall, no other company has anything resembling the SimplSeq purification method, Young said, and, on the assay prep side the technology combines "the ease of use that you get from AmpliSeq, combined with the improved data quality you get with a traditional targeted capture." The RNA capture is most comparable to DNA whole-exome and cancer panels, he said, such as Illumina's TruSight TSL 500 or TST 170. 

"We think that, in terms of rare samples, this will replace all of the purification modules and kits on the market," Young said. For the sample prep assays in particular, "We think that people are going to find that the data is higher quality, and also is much easier to run, at a cheaper price."

Incubation at Murrieta Genomics

Young's career has involved sequencing in clinical labs and core labs. He noticed that while sequencers and bioinformatics have evolved over the decades, sample prep had not changed much, and remains a major time drain and source of error.

But, constantly running samples in the lab doesn't allow much time to troubleshoot or invent new methods to overcome bench-side frustrations.

Young managed to connect with the team at genomics incubator Murrieta Genomics, became a cofounder, and has essentially been able to take a sabbatical to focus on inventing.

At Murrieta, Young said he has been removed from the "constant churn of producing data," and could develop these methods that he said increases the quality of the data, reduces errors, and takes away complicated, days-long steps.

Jay Goth, a cofounder of Murrieta, said the foundation of the incubator was inspired in part by its fortuitous location. Murrieta, California is equidistant from tech hubs like biopharma in San Diego, medical device startups in Orange Country, and other biotech in Los Angeles, but has the benefit of a lower cost of living.

Goth said he and another Murrieta cofounder, John Powers, had also determined that there were very few technology incubators or accelerators that were offering total support to entrepreneur biotech developers so that they might focus on their core strengths.

In contrast Murrieta is "like a mother hen sitting on an egg," Goth said. "We are trying to protect that egg from all of the elements until it is ready to break open the shell and get out into the world," he said.

To this end, Murrieta recruited its "secret sauce" advisory board, consisting of more than 30 experts spanning genomics and bioinformatics, and including physicians, researchers, intellectual property and corporate attorneys, and accountants.

"What we want to do is put the resources around these start-up companies that will cover everything ... and at the same time we have a lab where they can validate all of their science," Goth said.

Young noted that spending time on things like accounting, shipping, managing, and learning about patent law takes away from working out the science.

"The side that fails in startups isn't necessarily the idea, it's the business plan, and elements on the financial side," like renting space and purchasing equipment, Young said.

Murrieta gives its incubatees access to Illumina, Nanostring, and Oxford Nanopore equipment, Goth said, and allows startups to be able to develop something that is completely formed from the both the business and science perspectives before they start seeking investment funding.

Murrieta charges no up-front fees other than the hard costs of sequencing, Goth said, and then negotiates an equity percentage depending on how much work will be required to fully incubate the new company. This is usually in the 5 percent range but can go up to 20 percent if the nascent company requires more support from the board.

With SimplSeq, Goth said that Murrieta's due diligence has shown that it has a proprietary technology that is "completely different" than traditional commercial offerings.

Murrieta has helped SimplSeq sign memorandums of understanding with academic research labs, "and we have some large commercial labs that are very interested in what we are doing," Goth said.

Now, the incubator is seeking more scientists and entrepreneurs with "great genomics sequencing ideas, anywhere from diagnostics- to technology-related," he said, adding, "We are happy to talk to them."

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