NEW YORK (GenomeWeb) – Synthomics, a synthetic biology startup founded by Stanford University researchers, is trying to make oligonucleotide synthesis faster and cheaper than ever before.
Midway through a Phase II Small Business Innovation Research (SBIR) grant from the National Human Genome Research Institute (NHGRI), the company is convinced it has a product ready to sell to an emerging synthetic biology market.
"We have the taken attitude that we can miniaturize the reaction scale and make synthetic DNA less expensive, but also do it in a plate with individual wells," Synthomics President Keith Anderson told GenomeWeb.
Synthomics is making an instrument to build single-stranded oligonuleotides one base at a time on 1,536 well plates — 16 times more wells than a traditional 96-well format, which could lead to a 40-fold decrease in costs per base. Smaller wells mean smaller reaction volumes and less reagent use, but that's not the only reason the firm can get the cost down, Anderson said.
"Our innovation is to have what we call a monolithic solid support so it's not a collection of small glass beads, it's a single piece of polymer that we're synthesizing on," he said. "We can order it as single sheet and do bulk processing on it to have it prepared and ready for DNA synthesis."
Synthomics could also be faster than traditional DNA synthesizers. "Most of that is achieved because the equipment itself is very fast," Anderson said. It's an automated system that precisely dispenses small quantities of reagents on the plates. Anderson noted that the technology easily allows for the extraction of oligonucleotides from any of the single wells.
Anderson first conceived of Synthomics' technology while working as a senior scientist at the Stanford Genome Technology Center. He applied for a SBIR grant from the NHGRI and was awarded $135,100 to do a pilot study to see if the solid support technology was fundamentally sound.
"When making plastics like the plates, if you start miniaturizing features on those plastics, it actually gets more expensive to make them smaller," Andreson explained. "There was going to be a point if we are miniaturizing, it was actually going to make cost go up instead of down. We wanted to take a different approach to making plates and a big part of that was making the solid support we were going to use."
Anderson declined to describe the specifics of the solid support, but framed it against the existing technologies such as controlled pour glass, a technology that uses shards of glass with microscopic holes in which the nucleic acid synthesis takes place. "You need a method of trapping the powder to hold it still while dispensing liquid on it, otherwise the liquid will bounce out and move around. It literally could be jumping from well to well," he said. It's also expensive:
Anderson estimated that it would cost at least $75 per plate just for the controlled pour glass, and perhaps as much as $500 per plate. The polymer-based solid support, meantime, might cost less than $5 per plate, and is easier to work with.
"You can get it on huge rolls that are 2 feet to 3 feet wide and hundreds of feet long and dice them up from there, or get them pre-cut," Anderson said. It's also versatile and affords several ways of making the 1,536 well plates. "We can take the big sheet and sandwich it between a top and bottom layer of the plate and seal it in between or we can take the support and cut out a disc that's same diameter of well and stick it inside the well," he said.
Anderson also used that grant to test out a quality control system that he thinks will provide Synthomics with an even greater advantage over its competitors in the oligonucleotide synthesis field. "All the nozzles are monitored with a proprietary technology that we're going to file for some patents on quite soon," he said. The system validates the timing, location, and volume of every dispensation. "If we have even just one missed dispense, we can detect it and go back and correct that in an automated manner."
On the success of the Phase I grant, Anderson applied for and received a $1 million Phase II grant. With such a grant, the NHGRI expects a working prototype within two years, Anderson said. Synthomics is about halfway through that and already has a model that is routinely making oligos. "At any time we could tell NHGRI 'We have the prototype,'" he said.
Anderson frames the company as unique, even in the small field of companies trying to improve the process of producing oligonucleotides. He mentioned Twist Bioscience and Agilent, but said Synthomics is making a different product, even though they all make technology to synthesize DNA.
He said that Twist and Agilent were trying to make DNA on flat surfaces, not in microwells. "You can't individually select one [oligonucleotide] you synthesize from the many thousands you're making in parallel, you can't pull one out and do something useful with it, you have to do all 20,000 at the same time," he said.
"We can go cherry-pick off the oligos we are going to provide and reallocate them on a different plate," Anderson said. Harvesting is done with a standard alkalized gas vapor treatment to separate the oligos from the solid support and a simple water flush onto a new plate with the oligos suspended in liquid. "On a microarray you don't have the ability to do that. Fundamentally I think we're making a different product, and that is single-stranded DNA that you can handle individually. That makes a huge difference in the kind of end users you're able to attract," he said.
The killer application for Synthomics could be making DNA to be turned into synthetic gene circuits or even whole genomes. "There are a lot of efforts now … [to] engineer yeast and bacteria to produce naturally occurring drug products or engineer genetic food crops" using recombinant DNA technologies that are labor- and resource-intensive, Anderson said.
"Emerging genetic engineering projects are going to be able to make use of really inexpensive DNA and we can get [the price] down so low so that people can basically engineer genes or entire genomes from scratch using synthetic DNA and tiling it together," he added. Synthomics' platform would make shorter fragments between 20 and 160 bases long. Someone who's interested in building a gene would then purchase overlapping segments and use enzymes to stitch them together into much larger pieces, Anderson explained. Once they make larger pieces, they can make entire genes or replicate an entire genome from another organism, he said.
Synthomics, which is based in the Bay Area in Menlo Park, California, plans to commercialize its platform in the next year. How the firm actually generates money is up for consideration.
"If I had my way we'd give the box away for free and just have people have consumables contracts," he said. But the firm has also considered offering DNA synthesis as a service and could end up doing both.
Perhaps participants in its beta-testing period will be able to offer insight as to what would work best. Anderson said he has connections to several labs at Stanford that can serve as "ideal" test sites in the sense that "their goal is to publish and that would be win-win for everybody. Also, I think they have the right mindset to be putting in effort and participating in refining the machine."
Anderson said Synthomics has also been in talks with several potential customers, though he declined to identify them. The firm has also been in talks with angel investors and venture capital funds. "Getting some private investment makes sense for us," Anderson said.
In the meantime, Anderson is applying for more grants to diversify the firm's technology portfolio and invest in more advanced instrumentation as well as other products in line with DNA synthesis.
One potential area of expansion is enrichment probes for next-generation sequencing. "We think we could make those incredibly cheaply compared to competitors," Anderson said.