Companies like Ultima Genomics say they have the technology, which could lead to medical breakthroughs. But similar promises in the past have fizzled and barriers remain.
This article is part of Upstart, a series about companies harnessing new science and technology to solve challenges in their industries.
Sometimes the barrier to medical advancement isn’t in the science. It’s the money.
In 2003 the first full sequencing of the human genome — “an extensive and highly accurate sequence of the 3.1 billion units of DNA of the human genome,” as The Times put it — was completed; the project had started with a projected cost of roughly $3 billion (the eventual cost was deemed impossible to calculate). Even then, the idea that sequencing could be used to spot and prevent disease was raised — albeit not without skepticism. But with the monumental price of tests, few could afford them.
Over the years, as the underlying technology progressed, the price dropped, but not enough to deliver on the promise of so-called precision medicine, with drugs and treatments tailored to maximize effectiveness for each individual patient. With the price of a partial but useful genome scan hovering around $1,000, scientists believed big breakthroughs would only come when the whole genome sequencing cost sunk to around $100.
“One hundred dollars is the kind of money we are looking for,” said Dr. Bruce D. Gelb, a professor of genetics and genomic sciences at Mount Sinai Hospital in New York.
“If someone drops the price of sequencing 10-fold, I can sequence 10 times as many people,” he said. “And you build up your statistical oomph to discover stuff.”
The days of “statistical oomph” — meaning an explosion in the amount of data gleaned from lower-priced tests — appear imminent. Ultima Genomics, a biotech start up, made news at the Advances in Genome Biology and Technology conference in June, unveiling a gene-sequencing machine that it claims can sequence a complete genome for $100.
Whole genome sequencing for that price can potentially accelerate the development of a massive database that can be mined to find genes that cause illnesses, to shed light on the complex influence groups of genes have on one another and to detect genetic changes that indicate the presence of cancer before a PET or M.R.I. scan could.
This intersection of business and science may be as significant to business as it is to science. The sequencing market has so far been dominated by a single company, Illumina, whose patents are running out. And a flood of competitors offering new, comparatively low-cost gene sequencers, each touting its own advantages, is coming — although Ultima is the first company to deliver a $100 sequence.
The company is the brainchild of Gilad Almogy, a California Institute of Technology graduate trained in physics. The idea started percolating for Dr. Almogy after two personal experiences.
“I just felt that they were data starved,” he added.
Ultima sprang to life in fall 2015. At a bar in Menlo Park, Calif., Dr. Almogy was celebrating the sale of Cogenra Solar, a green energy company he founded with his lead investors, Vinod Khosla and Samir Kaul of Khosla Ventures, a tech investment firm specializing in early-stage companies. With the ink barely dry on the $65 million sale, Mr. Khosla asked Dr. Almogy what he would do next.
“Well, I’ve been dreaming of this product,” he recalls saying. Speaking over the din of the bar, he described how gene sequencing might be made cheaper and faster. Without even glancing at his partner, Mr. Kaul said, “We’re in.”
What lay ahead wasn’t a light lift. The machine Dr. Almogy envisioned would have to improve on three aspects of sequencing: optical scanning, which uses an automated laser-lit microscope; chemistry, which includes series of expensive reagents (substances used to spark chemical reactions) that make the individual bits of a gene visible; and data processing to generate, assemble and interpret the vast amount of information from the sample.
Optical scanning was Dr. Almogy’s field, “but the molecular biology, chemistry, sequencing side was not my background,” he said. He built a team of biologists and chemists through former employees, acquaintances and word of mouth, and then established a machine-learning and bioinformatics team based in Israel, his native country. The company’s staff grew to 350 employees this year.
A common gene sequencer works by affixing a DNA sample between two pieces of optically perfect glass called a flow cell. Different reagents are pumped over the sample hundreds of times per scan, making its components visible. Then, an automated microscope scans the length of the slide, stops at the end, shifts slightly and scans a new row — as if it were mowing a lawn. That collected data is processed for researchers and clinicians to interpret.
But the method slows the process, and the optically perfect glass and reagents are expensive.
In theory, Ultima addresses those disadvantages by replacing the rectangular flow cell with a silicon disk, which spins and allows the scanning microscope to operate continuously through each cycle, like a stylus moving across a vinyl record. This method also does away with the expensive optical glass cover. Reagents are applied to the center of the disk, and the spinning forces them to spread uniformly across the surface, reducing the need for expensive chemistry.
“There’s a massive industry that’s based around this 200 millimeter wafer, which we just made into our flow cell,” he added.
The savings are furthered by using less expensive chemistry and in lesser amounts, the company claims. Accuracy depends on the machine’s advanced machine learning.
While Ultima has set itself up as cost leader, a slew of other companies also offer new sequencers that put pressure on the market leader, Illumina. “Over the past couple of years there has been no competition, Illumina has had the lion’s share,” said Dr. Andrew Stergachis, assistant professor of medical genetics at the University of Washington in Seattle.
But now, “Illumina has a bunch of patents, and they are about to expire,” said Dr. Gelb. “Others are ready to move in.” Ultima has raised a reported $600 million in funding since 2015.
At the Advances in Genome Biology and Technology conference last June, more than a dozen sequencing and instrumentation technologies were announced, said Leisa Zigman, president of the Genome Partnership. Two sequencing companies that contended with Ultima for attention were Singular Genomics and Element Biosciences, whose sequencers are in the $300,000 range, and compete, they say, with units that are currently $1 million. (Ultima has not revealed pricing, although it said it has sold units.) Illumina recently announced a new line of machines that would deliver a complete sequence for $200.
As exciting as the scientific community finds this, it remains to be seen how the newest sequencers will perform with so few of them sold. “The $100, $1000 or $10 genome makes a great headline,” acknowledged Molly He, founder of Element Biosciences, “but what counts is what is actionable, what can be applied at the bedside.”
Ultima has faced some skepticism because of a known issue sequencing homopolymers, which are consecutive identical bits of genetic material. “Every system has different gaps,” Dr. Almogy said. The 11 customers who have purchased or placed an order, he claimed, are “fully aware” of the issue and deem it unimportant to them.
Some practitioners are not so sanguine. “Is this ready to go?” Dr. Gelb said. “The answer most people have is, ‘We aren’t sure.’” Gaps or errors in sequencing could lead to results that aren’t sufficiently clinically accurate.
Another reason for skepticism: $100 sequences have been promised before — MGI Tech Co., Ltd., a genetics company based in China, did so at the A.G.B.T. conference in 2020 — but have yet to materialize.
Critiques aside, scientists foresee a combination of new technology and new competition further driving down the cost of sequencing an entire genome. And many see a major transformation in research and medicine as a result.
However, money still creates a barrier. Insurers currently pay for sequencing only in limited circumstances, and sometimes only after tens of thousands have already been spent on other inconclusive tests.
“Insurance will not pay for a test that is not ‘medically necessary’ unless there is high-quality evidence of both clinical utility and improved value for health compared to current practice,” Dr. Marc S. Williams, president of the American College of Medical Genetics and Genomics, wrote in an email.
Much more research is needed to reach the point where genome sequencing becomes a ubiquitous part of a checkup. But cheaper sequencing is a critical first step.
“We really see this as transformative,” said Dr. Eric Green, director of the National Human Genome Research Institute, which is part of the National Institutes of Health. However, he cautioned, “I can’t think of a single example of a significant development in science that changed the practice of medicine measured in anything less than multiple decades.”