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Advanced technology for sequencing genomes could change healthcare’s foundation
It happened so fast—moving from an era when sequencing one gene earned a Ph.D. to a day when sequencing got fast enough for clinical applications. That change emerged from significant improvements in technology. “Over the last 5–10 years, costs [of and the time required to sequence] have declined dramatically,” says Gregory Cooper, faculty investigator at the HudsonAlpha Institute for Biotechnology (Huntsville, AL). “While the rate of decline has slowed somewhat recently, the improvements relative to the early days of exome sequencing—about eight years ago—are tremendous and have led to technology costs that are comparable, in general terms, to that of many complex medical tests, such as MRIs.”
Instead of just sequencing the exome, today’s clinical studies and diagnostics can consider the entire genome with whole genome sequencings (WGS). “The costs of WGS have declined to the point where it is displacing exome sequencing in many clinical contexts,” Cooper says.
Clinical sequencing remains on the rise around the world. “The rapid expansion of both noninvasive prenatal testing (NIPT) and multigene panels has been the driver for growth in the clinical-sequencing space,” says Lori Aro of Pacific Biosciences (Menlo Park, CA). “Infectious-disease testing for microbiology is an emerging hot area for clinical sequencing.” This goes beyond the already well-known applications, such as using sequencing to diagnose and pick the best treatment for various cancers.
Verifying the variation
The DNA (blue) in these human breast cancer cells could be sequenced to help clinicians better understand the disease and, possibly, how to treat it. (Image courtesy of the NCI Center for Cancer Research, National Cancer Institute, National Institutes of Health.)To make valuable clinical use of sequencing, scientists must know what is normal and what is abnormal, and that requires more knowledge about the variation in genes across populations. “Data about the extent and distribution of genetic variation within humans has increased dramatically, which facilitates more efficient and effective variant interpretation,” Cooper explains. By looking at the genomes of more people, scientists learn about the frequency of gene variation.
Today’s data environment changes what is possible in analyzing genome data. As Cooper says, “Data sharing—a longstanding tenet of basic genomics researchers and communities—has also grown and become more deeply ingrained outside of genomics and into medical genetics and other related fields.” He adds, “Data sharing, especially for rare-disease analysis, is crucial to progress.”
As scientists find more variation, clinicians face increasing challenges to understand this variation and to make use of it. With insertions, deletions, and single-nucleotide polymorphisms (SNPs), the information in variation can be staggering. “Our understanding and ability to predict the functional effects of many variants, including both protein-altering and noncoding variants, also needs to greatly improve to lead to better disease—or other clinical consequence—prediction,” Cooper notes.
To make that information useful to everyone, scientists must sequence diverse populations. Otherwise, only certain groups will benefit.
Seeking speed and more
The FEMTO Pulse is a capillary electrophoresis platform that can quantify and size DNA fragments up to 165,000 base pairs, which allows it to handle quality control for long-read sequencing applications. (Image courtesy of AATI.)As the basic technology of gene sequencing improves, the need for speed moves to different areas. Software and infrastructure must connect the genetic information with clinicians. This information must be simplified enough to be understandable, but not so simple that it’s inaccurate. “Basically, we need to be able to extract bits of genetic information when and where they are relevant without overwhelming patients or providers,” Cooper notes. “An example is that WGS information on a given patient might contain a number of results relevant to correct drug dosing and response, but if that information is not made available when and where the patient is given a prescription, then it can’t be used effectively.”
Making more use of clinical sequencing is not all about speed. When asked what changes in technology make clinical sequencing more widely used, Aro’s first reply is: “Accuracy—innovative technology advancements, such as long-read sequencing that produces the highest consensus accuracy and uniform coverage.” If the sequence is not right, it’s worthless.
Even with the right sequence, scientists and clinicians need to keep learning what information can be used clinically and how. When asked about the changes in technology that are making clinical sequencing more widely used, a group of spokespeople from Illumina (San Diego, CA) pointed out that a “growing body of clinical trials demonstrate the utility of next-generation sequencing.” They also noted the value of multiplexing to simultaneously sequence more than one sample.
Missed opportunities
A little reading in the medical literature quickly reveals cancer drugs that zero in on specific gene-related targets. Some of the work makes it sound like certain cancers can be treated long term with these amazing methods. But that requires doing the genetic testing.
The Illumina group agrees that this is a problem. When asked about places where clinical sequencing should be used now but isn’t, they answered: “routine oncology testing to elucidate tumor biology.” With today’s capabilities, if someone has a tumor, someone should sequence it.
The Illumina team added that sequencing should be used “in all pregnancies, instead of high risk only, despite overwhelming clinical evidence.”
Knowing more from sequencing only matters in the clinic when it gets used. Also, the sample’s quality must be considered. “In DNA and RNA extraction,” says Steve Siembieda, vice president of commercialization at Advanced Analytical Technologies (AATI, Ankeny, IA), “there can be inhibitors that affect subsequent molecular-biology steps and procedures.”
That means that samples should be tested for quality before being sequenced. Although some experts suggest assessing the quality of any nucleic-acid sample before sequencing, some labs decide based on the sample—less likely for blood samples and more likely for formalin-fixed tissue samples. As Siembieda says, “The tissue type, sample preparation, and handling methods all impact the DNA quality.”
The quality-control step can cost as little as a few dollars per sample. In the future, Siembieda speculates that quality control could be integrated with sequencing platforms.
Ongoing obstacles
As sequencing technology continues to advance, scientists and clinicians must continue to educate themselves. Education is also valuable for the community at large. “As testing increases, so too do the chances that any given person will at some point become a patient for which genetic information is clinically important,” Cooper explains. In such cases, patients must educate themselves if they want any chance of proactively maintaining their own health.
Clinical sequencing also raises legal and privacy concerns. The immaturity of this field makes these problems particularly relevant today. Nonetheless, such challenges could continue. For example, how will this information be used by insurers? If not protected properly, clinical-sequencing information could be used against patients instead of for them.
As much as clinical sequencing might amaze people today, tomorrow’s uses could be even more startling. As Cooper points out, “Eventually—likely well past five and probably even 10 years from now—I believe that WGS will occur routinely at birth and become part of a permanent medical record that can subsequently be used whenever a clinical problem to which genetic information is relevant—of which there are many—arises.” Only then will scientists truly know the potential of clinical sequencing to change lives.
Mike May is a freelance writer and editor living in Texas. He can be reached at mike@techtypercom.