James Lu, MD, PhD, has been interested in the intersection of clinical care and genomics since the early days of next-generation sequencing (NGS) and the dawn of personal genomics in the mid-to-late 2000s.

“In the early days of NGS, a lot of the early problems in that space, before Illumina became dominant, were around signal to noise—essentially, how do you identify a variant to make it useful and valid?” Lu told GEN Edge, in his distinguishing shrewd and ebullient quick-firing manner. “I’ve been around the space for a reasonable amount of time, particularly focused on this intersection: how do you drive genomics into clinical care?”

The reason Lu believed that genomics would imbue healthcare has to do with how he categorizes health determinants: environmental (access to clean running water and medicine), behavioral (drinking soda and eating donuts), and inherited genetics and biology. “The first two are easier to ascertain,” said Lu. “I can ask you where you live or about your behavior. Generally, those are easier questions.”

However, genetics and biology have historically been difficult and expensive to capture at scale, often requiring a very narrow question. “If you think about managing population risk—and, frankly, the transition of care from fee-for-service to value-based care over time—you’re going to have a problem if you miss a third of the risk,” said Lu.

Lu spotted that genomics would become a macrotrend in healthcare, permeating healthcare, even primary care, in all the ways radiology has over time. “It’s only been in the last couple of years that suddenly the technology has progressed, both on the sequencing and the computational sides, and that the knowledge base for the genetic pool of data is now accessible for population-level work,” Lu said. “Genomics will become the standard of care, and that’s largely become a question of when not a question of if anymore.”

He began to dream of a world where genetics will provide a real-time response versus one that takes weeks, to drive down the cost of care, as running an assay is often more expensive than a computer query. He set his sights on how to offer top-tier provider and patient experiences by making genomics a part of the healthcare fabric.

So, after one year as a faculty member of electrical and computational engineering and the department of medicine at Duke University, a conscientious Lu left academia and started the population genomics company Helix in 2015 in San Mateo, California.

The clinical genomics lab of tomorrow

Helix is a familiar name to many San Diego residents, known for its partnership with the county to make COVID-19 testing accessible, through which it provided up to 12,000 COVID-19 tests per day during the peak. With just 265 employees, it also handled up to 40,000 tests per day for people nationwide, through its lab in San Diego. Those numbers are smaller today, but it still processes COVID-19 tests. The company has also made a splash for its partnerships with the CDC, including a collaboration announced in September 2022 to sequence more than 3,000 SARS-CoV-2 samples per week for the next year to expand the CDC’s testing capacity to monitor viral mutations for vaccine escape, transmission changes, and outbreaks.

But viral surveillance is not what Lu set out to do with Helix, which aims to accelerate the integration of genomic data into patient care and public health decision-making. For genomics to become the standard of care, Lu believes that the first step is to achieve sequencing at scale with high-quality data at a low cost. So, after setting up the main lab in San Diego—where the expeditious CEO flew into for a few hours to do an interview and a handful of meetings before heading back to headquarters in the Bay Area that evening—Lu brought on Marc Laurent, who spent a good chunk of his 16 years at Illumina being operationally responsible for Illumina Genomic Services, one of the world’s largest NGS centers and the first CLIA-certified and CAP-accredited clinical lab, to deliver whole genome sequencing results to physicians and patients. Soon, Helix will have a new lab in the Sorrento Valley area of San Diego that will be 32,000 square feet to accommodate Helix’s growing scale.

Now vice president of partnerships and operations at Helix, Laurent believes that there is no single system, instrument, or kit that can be used on its own to work sufficiently to make NGS work at scale. He created an automated clinical-grade lab at Helix containing all sorts of machines to efficiently run essentially one assay: whole exome sequencing (WES). The lab is very module-based and has very large batch sizes. “We use many independent machines that together create a highly functional assay that we run very efficiently as a factory,” Laurent told GEN Edge. “We found out that the best way to do it and get the best economics was to essentially take the parts that we like the best from, and we have a tremendous amount of bioinformatics and data management for all of the physical samples moving around and the data coming out of it.”

Helix WES Assay
A clinical laboratory scientist operates a module of Helix’s panel-grade clinical Exome+ assay. [Helix OpCo, LLC.]
When asked why Helix went the route of WES over looking at an entire genome, Lu rapidly responded that in the clinical space, almost everything known today sits in the coding regions, which are the questions Helix is most interested in answering. That being said, the Helix assay does incorporate some non-coding regions. “If you truly believe that [sequencing] is a thing you hopefully only have to do once or twice in your life, then you need to make sure you’re as future-facing as possible,” said Lu. “Our assay is designed to be future-facing and still have the right set of economics to make these things viable.”

“Our capacity is inherently quite large, and so we can afford to not run it at 100% all the time because we don’t have people waiting for samples,” said Laurent. “That allows us to have some excess capacity to take the ups and downs and keep our turnaround time constant. We’re able to plan ahead and build capacity as it comes along.”

Once a broad scope of genomic data has been generated, the next step is to figure out how to quickly and easily transition its use into practice. Lu believes that the WES results need to trigger something that’s interventional, doesn’t create a lot of false positives, and can convey certainty to the patient’s providers.

Based on WES data, Helix is currently taking a narrow look at the diseases that are part of the CDC Tier 1 genomic application toolkit. This set addresses the nearly two million people in the United States who are at increased risk for adverse health outcomes because they have genetic mutations that predispose them to one of three conditions: Hereditary Breast and Ovarian Cancer Syndrome (HBOC), Lynch Syndrome (LS), or Familial Hypercholesterolemia (FH). At present, these conditions are poorly ascertained by the healthcare system, with many individuals and families affected by them not aware that they are at risk; however, early detection and intervention could significantly reduce morbidity and mortality.

For the provider side, Helix has essentially kept things unchanged and has helped the health system establish a process by which they will collect the sample from the patient. According to Laurent, “As you go downstairs to go to your phlebotomy lab, you also get an extra tube, This way, providers are advocates of the program but don’t have much more added to their workflow.”

Helix ultimately receives either individual samples through the mail or large bulk samples from the health system’s blood-saliva mix. This sample is sent to the lab to sequence the exome plus all the additional data that comes with it, analyzed, and returned with the clinical data and CDC Tier 1 report to the physician, who then delivers it to the patient. The data can then be archived but be ready to be queried again, whether they want to do pharmacogenomics today or have a cardiology question ten years from now when they have another risk that they’re concerned about, or if the science has advanced and can offer more insights.

Making population genomics foundational

To deliver genomics as a data stream or operating system within healthcare, Lu thinks the best way is to work with health systems. “Most of our partnerships are with large-scale health systems and are focused on large-scale population-level programs,” said Lu. “Typically, 100,000 people plus, where they inevitably believe that this is going to become the standard of care over time.”

Over time, health systems want to drive the cost of care down while improving the quality of patient experiences. Lu hopes that by working with Helix, health systems will be able to identify patients who are clearly at risk and are hiding in plain sight that they should manage today, like carriers of well-established deleterious DNA variants. These data could also enable the health systems to develop new population health and value-based care algorithms to manage the health of broader populations. “The key thing we think about is care transformation, coordination, and gap closure—not the ‘sexy’ things of genetics, but the bread and butter of healthcare.”

Currently, Helix has several major programs across the country that represent more than 100,000 people. “I think we represent the largest-scale programs in America now across health systems,” said Lu. “There are only a few independent programs now that are not partnered with Helix, and we really think of ourselves as a supporting organization for health systems to transform their care.”

Since healthcare is longitudinal, it’s important to make the data that Helix turns over to be the most impactful now and down the line. “If you give everyone all their pharmacogenetic information today, but they’re not taking any drugs, who cares?” said Lu. “Realistically, no one is going to remember that information five years from now. But if you start taking several drugs and something happens, then you do care, and that data is highly relevant.”

The questions that physicians usually hit Helix with often pertain to the limited time they have per patient visit. If a provider only has 10–12 minutes with a patient, how quickly can they pull up the genomics information and make it actionable? Helix is working to bring that data to them in the moments when they will actually use it, and support physicians so that they can interact with the data and deliver the right type of care to that patient without having to overwhelm them with the history of their genetics.

“My guess is most of genomics is going to go away from medical genetics,” predicts Lu. “It will go into internal medicine and primary care, and they’ll be able to answer the right question.”

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