By Julianna LeMieux, PhD

Ultima Genomics has been quiet since the June 2022 Advances in Genome Biology and Technology (AGBT) conference, where the company boldly entered the next-generation sequencing (NGS) world by introducing the UG 100 sequencing instrument. At that AGBT meeting, the UG 100, which was ensconced in Ultima’s suite, attracted a swarm of onlookers. The instrument was one of several new tools introduced last year, including platforms from more established companies.

Gilad Almogy
Last year, this photograph of Ultima Genomics’ CEO, Gilad Almogy, enjoyed wide circulation in the press. The occasion? Ultima had just emerged from stealth mode. The company had posted several bioRxiv preprints, announced $600 million in new funding, and claimed that it could sequence a complete human genome for $100. Since then, Ultima has stayed relatively quiet. But now that Ultima is preparing the commercial launch of its UG 100 instrument, the company will soon reenter the limelight. Its desire for more attention was recently confirmed by the announcement that Ultima is this year’s Gold sponsor of AGBT 2024.

At this year’s AGBT conference, Ultima was anything but conspicuous. There was no instrument, no suite, no swarm of onlookers. Yet I managed to get an update, if only by chance, from Gilad Almogy, PhD, the company’s CEO.

Almogy had been riding an elevator, likely heading to or from an AGBT-related meeting, when I greeted him and proposed an impromptu interview. Happily, Almogy agreed. Even better, when we met later, he responded to my questions with straightforward answers. (On this occasion, he was unaccompanied by staff members interested in translating his answers into marketing speak.)

In a disarmingly earnest manner, Almogy told me that his company’s lack of fanfare did not indicate a lack of progress. He explained that Ultima had been holding closed-door meetings and staging events to learn what early-access customers had to say about the UG 100.

I asked Almogy, who studied quantum optics and spent years developing semiconductor-based diagnostic instruments, how he felt about his new field, genomics. He responded quickly, “I love it.” The world of semiconductors, he said, was great fun because it was constantly moving. That world would transform every two years. But he grew ever more detached from the applications. He found it hard to feel excited about developing a better inspection tool that would, for example, allow people to program better games for teenagers.

Almogy doubts he’ll miss the thrilling speed of the semiconductor field now that the genomics field is becoming increasingly competitive. “It’s a technological arms race,” he said. It’s not only challenging and exciting from a technological view, but it is paired with customers that are “insanely smart” and working on gratifying projects.

Ultima Genomics in Fremont, CA
The production facility that Ultima Genomics occupies in Fremont, CA, could hardly look more ordinary. But that doesn’t bother Ultima’s CEO, Gilad Almogy. If he wants to appreciate architecture, he ignores the facility’s exterior and instead fixes on the company’s sequencing platform, which reflects novel design principles. Ultima Genomics indicates that it has developed an architecture for sequencing instruments that reflects innovations in flow cell engineering, sequencing chemistry, and machine learning, and that is capable of scaling beyond conventional sequencing approaches.

Almogy likens himself to the proverbial kid in the toy store. Genomics, he points out, is where everything converges: biology, data, and technology. “Maybe I’m biased,” he continued, “but I couldn’t imagine being anywhere more exciting.”

In that same conversation, Almogy invited GEN to visit Ultima in South San Francisco. A few months later, I found myself pulling up to the Ultima building.

Seeing the tools

When I reached Ultima’s facility in Fremont, CA, I wondered if I was in the right place. I had started to think that everything about the company was big. It had a staff of 400 people. It had raised $600 million since 2016. It had built a machine that was large enough to command attention. So, I had expected to see a big, impressive building. Instead, I saw a nondescript, single-story building in an industrial park.

Almogy soon arrived and told me that Ultima is in transition. For the past few years, the company has been renting space in Newark, CA. Soon, all company activities will move to new headquarters in Fremont—near the production site that I was visiting. It was modest, but Almogy was unapologetic.

“[I thought] it was more important for you to see the tools than the [corporate headquarters],” he said. “We like to spend our resources where it matters.”

At some point during our conversation, Almogy decided to show me a wafer from one of the company’s instruments. (An Ultima wafer is akin to other sequencing companies’ flow cells.) He reached into his bag, apparently expecting to find one in there. The gesture looked perfectly natural. If you sleep, eat, and breathe DNA sequencing, why not carry it around, too?

The beginning

When Almogy first had the idea to build a DNA sequencer, he asked for input from NGS users. They provided “screaming feedback” about the need for “more data” and “lower costs.”

Upon starting Ultima, Almogy had a basic understanding of what was needed to build a sequencer that could shake up the high-throughput sequencing space. He needed to make two fundamental changes to existing platforms: faster chemistry and a flow-based system with no fluorescent terminator. He leaned into his background in diagnostics and semiconductor chips. In his old field, he developed systems (still in use today around the world) that were fast and, thanks to the design of the underlying architecture, capable of becoming faster every few years.

Ultima, Almogy decided, would blaze a path different from that taken by other NGS companies. Ultima would build an economical and automated sequencer, one that would be capable of continuous operations and suitable for high-volume users. It wouldn’t even look like a regular sequencer. Shrugging, Almogy acknowledged, “We took on a lot.”

Ultima’s UG 100 sequencer
Gilad Almogy, Ultima Genomics’ CEO, proudly displays what he calls an “open flow cell.” This circular 200-mm silicon wafer is a key component of Ultima’s UG 100 sequencer. It harbors a dense array of sequencing beads, and when it spins, reagents dispensed near its center are spread over its surface by centrifugal force. Then, optical scanning of the rotating surface is performed continuously, in a process analogous to that used for reading a compact disk.

Now, Ultima is in the last stages of its early-access program, with plans to launch by the end of 2023. When that happens, the time for tweaking, fine tuning, and responding to the suggestions of early-access customers will end. The UG 100 specifications will be locked in. And Ultima will wait to see how the market responds.

Quantity means quality

Ultima declined to share its complete list of early-access customers. However, the company did say that the number of customers on the list was in the mid-teens. The company also disclosed that customers on the list included Genome Insight, the Broad Institute, Baylor University, the New York Genome Center, Exact Sciences, and Regeneron Pharmaceuticals.

All of the early-access customers (and other potential customers) are gated by their current scale of sequencing, Almogy remarked. He observed that although everyone wants to pay less, the opportunity is driven more by customers’ desire to do more. He elaborated, “I haven’t yet come across any field where people don’t want more data.”

“Every [person] will have a whole genome sequence—that’s a given,” he insisted. But that’s someone’s germline—the DNA sequence they’re born with—not how it’s changing. What is happening to your mutation profile or methylation profile—that’s not static. And that data, Almogy stressed, will become a bigger and bigger part of healthcare.

This cost of sequencing will have a big impact on moving this field forward. Ultima believes that cost is the biggest pain point. That might not be the case if you’re running a flow cell every other week. But for high-volume users, cost is a major concern. And it’s one that might justify the cost and inconvenience of switching to a new instrument.

According to Almogy, sequencing will be here for a very long time. Indeed, he pointed out that many trends are driving the need for much more sequencing. He predicted that the amount of sequencing that will be generated annually in the future will increase this year’s figure by orders of magnitude.

Ups and downs

When Ultima first unveiled the UG 100 some 15 months ago, the instrument sparked a lot of interest—and a healthy amount of skepticism. Some questioned whether the UG 100 would be able to accurately sequence longer homopolymer regions. But Ultima insists that the version of the UG 100 that will hit the market shortly will be much better than the 2022 version. How much better? Without offering details, Almogy assured me that I won’t be writing about homopolymers next year.

Almogy also touted the sequencing accuracy on single-nucleotide polymorphisms (SNPs.) “We have higher accuracy than every other sequencing platform when it comes to SNPs,” he asserted. In other sequencing platforms, the four bases flow together, and the instrument identifies or “calls” the nucleotide. But if it is wrong, there is no going back. There’s a single shot on goal. By contrast, the UG 100 has multiple shots on goal because it is flow based.

Another advantage (for high-volume users) is that the instrument will be able to run continuously, 24/7. Rather than just one box, the UG 100 has a separate prep box for DNA amplification. Although some may view this as a disadvantage, Almogy notes that this feature allows users to amplify whenever they want. And because multiple samples can be loaded into the UG 100, it will pick them up and start a run—even in the middle of the night.

Ultima has yet to release a lot of specifications. But it notes that the run times are less than 20 hours, the average read length is around 300 base pairs, the accuracy is Q30 > 85%, and the cost is $1.00/Gb. Almogy credited a series of advances with bringing the UG 100 to this point—improvements in chemistry, coverage (accessing more of the genome), base-calling algorithms, and variant calling.

Almogy stated that Ultima is not a one-trick pony, and that it is not stopping at the UG 100. The company, he pointed out, will take advantage of the scalable architecture it has developed—an architecture that could help DNA sequencing sustain its march down the cost curve.

I asked Almogy if he has his sights set on other omics fields like spatial omics or proteomics. “Our core strength,” he answered, “is making sequencing cheaper and cheaper and better and better. That’s what we do.” When Almogy showed me the production floor, his demeanor lightened for a moment as he explained the inner workings of the instruments. The “kid in a toy store” saying comes to mind. And his smile lets you know that he has relaxed—just a little.

A crowded field

When asked about the competition, specifically the arrival of two high-throughput systems (Complete Genomics’ T20x2 and Illumina’s NovaseqX) over the past year, Almogy responded that “it’s great for the industry.”

Ultima doesn’t pay much attention to the mid-throughput sequencing competition. “They don’t pay attention to us either,” Almogy remarked. But Ultima’s chief financial officer, David Peoples, sees it a little differently. “I think they pay attention to us because we’re driving the cost of sequencing down, which could have a broader impact on the market.”

The cost of DNA sequencing is finally going to get unstuck, Almogy maintained. This will accelerate the transition to larger panels and deeper sequencing. It also pushes the notion that we’re not happy with the amount of sequencing we have and that we need more sequencing. Illumina dropping its price by a meaningful factor does not mean that people will spend a lot less money with them. They’ll just consume a lot more genomic information.

“I think it’s great that we’ve maybe played our part in stoking competition,” Almogy declared. “And if we played a small role in [pushing prices down], I’m very proud of that.”

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