It’s been a little more than one year since Illumina broke ‘the sound barrier of genomics’ by enabling the world’s first $1,000 genome with the launch of the HiSeq X Ten Sequencing System. Since then, the industry and the world have seen an increase in the number of research programs that utilize whole genome sequencing (WGS) – including Prime Minister David Cameron’s announcement of the 100,000 Genomes Project in the UK and the Obama Administration’s Precision Medicine Initiative.
While these types of programs are growing across the globe, so is interest in individual sequencing for medical and wellness purposes. But the two – research and clinical sequencing – have significant differences. Tina Hambuch, Ph.D., FACMG, director of Illumina Clinical Services, and Tonya McSherry, product manager of Illumina Genomic Services, outline the distinctions.
For research use only
Large academic centers and institutes are typically the drivers in WGS for “research use only” (RUO) projects. At Illumina, RUO sequencing is either done through partnering with labs including members of the Illumina Genome Network (IGN) or an Illumina CSPro (certified service provider), HiSeq X Ten customers or Illumina’s Fast Track Sequencing Services.
IGN links researchers interested in conducting large human genome sequencing projects with leading institutes worldwide that provide highly economical and rapid turnaround access to Illumina sequencing. IGN members include British Columbia Cancer Agency (BCCA), Genome Sciences Centre, Broad Institute, Cold Spring Harbor Laboratory, HudsonAlpha Institute for Biotechnology, Macrogen Clinical Lab, McGill University and Génome Québec Innovation Centre, National Genomics Infrastructure, Science for Life Laboratory, New York Genome Center, Northwest Genomics Center, University of Washington, Novogene Bioinformatics, Takara Bio, Inc., and the Yale Center for Genome Analysis.
Clinical services at the forefront
Illumina has been providing high-quality DNA analysis services to the research community since 2001. In 2009, it established a CLIA-certified, CAP-accredited clinical laboratory, Illumina Clinical Services Laboratory, for the purpose of offering human WGS services to physicians. This laboratory is staffed with a team of experts, including board certified medical geneticists, genetic counselors and clinical laboratory scientists who have training and experience with Illumina next generation sequencing (NGS) technologies. In fact, the Illumina Clinical Services Laboratory was the first to generate a personal genome sequence in a clinical laboratory setting in 2009.
Among the options within the clinical lab, doctors can order a TruGenome Undiagnosed Disease test to identify the underlying cause of a genetic condition or a TruGenome Predisposition Screen intended for healthy adults, over the age of 21, interested in learning about their risk for a specific set of adult-onset conditions, assessing their carrier screening status, and understanding their response to certain drugs.
Same technology, same price?
While Illumina’s service offerings for research and for the clinic are different, they are both built on Illumina’s sequencing by synthesis technology. Thus, the technology that enabled the $1,000 genome is the technology being used for both research and clinical purposes. So, why can’t an individual get sequenced for $1,000? Tina Hambuch points to efficiencies of sequencing on a mass scale as is done on a HiSeq X Ten. “In order to achieve the $1,000 genome, you’re running a lab all day, every day, to maximize utilization.”
There are many considerations that factor into the cost of sequencing a genome. Research projects involve a large amount of samples, whereas clinical sequencing deals with individual patients and samples.
Hambuch adds, “In terms of processing, every case that comes into the clinical lab is not part of a bigger project. For the TruGenome Clinical Sequencing Services we can’t batch, we can’t scale; so we don’t benefit from some of the efficiencies of scaling the way a research oriented service can, because we cannot wait to gather a bunch of samples. As soon as the patient sample comes in, we have to start processing it by itself. So there are some added expenses around having to operate in that way.”
Perhaps the most important distinction is the “end result” or main deliverable for clinical purposes as compared to RUO. In a research service lab, the final deliverable is a summary of all the positions in a sequenced genome that are different than the reference genome. In contrast, in the clinical lab, the final product is an interpreted report.
As Tonya McSherry explains, “It’s a question of whether a doctor is looking for guidance for a diagnosis or treatment, as compared to research where it’s about identifying the underlining genetic background for a range of applications from diseases to populations.”
Hambuch agrees. “The final step that has a lot to do with the cost of sequencing a genome for clinical purposes is actually analyzing that genome to give a clinical report that can try to answer the question that was being asked in the first place. If the question is, ‘Can you find a reason for this child's symptoms?’ we need to go into that genome and do a fairly extensive evaluation of all of the variants that we see and their clinical implications. And that, of course, adds to the price of the product that we're delivering.”
Hambuch cautions, though, that in the clinical lab, the primary focus isn’t achieving the lowest cost genome possible. She explains, “In our lab, it's going after the highest quality, most comprehensive genome possible. Our focus is to increase the number of genes that we can report on, how quickly we can report on those genes and the types of variants we are detecting. Our goal is to increase the clinical sensitivity of the test we are offering significantly. We are constantly trying to develop new ways to optimize the information we're getting from the genome and maximize that. Right now that's where our focus is, much more so than driving down a price.”
Coming full circle
While it is necessary to make distinctions between RUO and clinical WGS, it’s important to note the synergies between the two and how they are intertwined. As McSherry explains, “All of the discovery work that happens in the RUO space will ultimately lead to better understanding of the genetic background and how that could lead to more genes that we report on in the clinical space.”
And both agree it’s happening at an incredible rate.
“In the early 1990s, we’d mapped out five or six genes that people were looking at clinically on a regular basis. Contrast that to 25 years later and it’s more like 2,800 genes,” states Hambuch. “We’re at the beginning of a huge exponential growth in understanding, thanks to all the research that’s being done and the fact that these tools are enabling us to look and discover.”