Saphyr, a recently discovered tool used by researchers collaborating across the globe, could be useful in predicting which COVID-19 patients might experience lingering symptoms. The technology serves to identify structural variations (SVs) in an individual’s DNA that could make them vulnerable to long-term cases of the virus.
Outsourcing-Pharma (OSP) recently discussed the project with Erik Holmlin (EH), CEO of Bionano Genomics, who told us about the technology’s history, clinical applications, and its potential utility in delivering the right treatment to the right patients.
OSP: Could you please explain what a COVID “long hauler” patient is?
EH: COVID “long haulers” are patients who have seemingly recovered from an initial COVID infection but continue to experience symptoms. Because COVID-19 infection can significantly impact a patient’s respiratory system, many of the lingering symptoms associated with long-haulers tend to continue impacting the airways, although other symptoms have been reported as well.
While anyone infected with COVID-19 can be a long-hauler, elderly and immunocompromised patients continue to be considered higher risk of developing longer-term complications.
OSP: What are the most common lingering symptoms, and do they vary by patient?
EH: Researchers and healthcare professionals are continuing to collect data around COVID-19 and how this virus impacts patients. While symptoms can certainly vary from patient to patient, the majority of “long hauler” symptoms tend to involve the airways as COVID-19 is a respiratory infection.
Some common “long hauler” symptoms include shortness of breath, cough, chest pain and fatigue. Given the variability between reported symptoms in patients, researchers and doctors have not been able to create a definitive profile of "long-haulers" to date.
OSP: In general, what do researchers know about genetic vulnerabilities to COVID-19 infection?
EH: We have already witnessed many cases of patients who were seemingly healthy, with no significant underlying health issues, experience severe and sometimes deadly complications as a result of COVID-19 infection. On the other hand, there have been many individuals exposed to the virus who never went on to experience complications and remained asymptomatic.
There is growing evidence that genetic differences between these two groups can predispose to a mild or severe disease case. These differences tend to be genetic and often SVs in genes affecting the immune system and influencing pathways that control cellular response to viral infection.
If we can better understand how genetic variations can contribute to disease severity, or how genetics possibly affects response to treatment or a vaccine, that can help inform development of more effective treatments and vaccines.
OSP: Could you please provide a little more detail about SVs, and their relation with disease severity?
EH: SVs are large-scale rearrangements of chromosomal DNA, sometimes as large as millions of DNA bases in size. These variations can include deletions, duplications, inversions or translocations of DNA and are often so large or complex that they are undetectable using other advanced genome sequencing techniques like whole genome sequencing and single-nucleotide polymorphism (SNP) analysis.
SVs often have a large impact on disease development or progression. Due to their size they are more likely to disrupt normal gene function than smaller mutations or variations.
These disruptions give rise to disease or could change how an individual responds to certain treatments. SVs are known to be strong predictors of the severity of many types of cancers, especially blood cancers such as leukemia.
SVs are also known to contribute to developmental delay disorders, pediatric genetic disorders, and as we've been exploring more recently, an individual's susceptibility to certain infectious diseases, such as COVID-19.
OSP: Then, please tell us a bit about the Saphyr tool—what is it, how it works, and what advantages it offers researchers over more conventional genomics tools, etc.
EH: Saphyr is a genome imaging instrument that serves as an SV discovery platform. Conventional genomic tools such as next-generation sequencing (NGS) systems have poor sensitivity to detect SVs.
Saphyr's images ultra-long, linearized DNA molecules labeled at specific sequence motifs. The label patterns on these megabase-length molecules are then compared to the reference genome to reveal SVs, similarly to how banding patterns on chromosomes are analyzed during karyotyping, but with one thousand times higher pattern density.
Saphyr’s advantage over sequencing techniques is that it analyzes much larger pieces of DNA, which makes the system able to span the many large repeats in the genome and identify and characterize SVs at high sensitivities with extremely low false positive rates.
These large SVs, which are often missed by other molecular methods, are responsible for many diseases and conditions including cancers and developmental disorders. Saphyr is streamlining cytogenomics with a simple and inexpensive workflow. It has demonstrated 100% concordance to traditional methods – microarray, karyotyping and FISH in multiple different studies while consolidating much of the information obtained from these assays into one system.
OSP: Can the tool be used for other diseases?
EH: In addition to COVID-19, Saphyr can be used for discovery research as well as clinical diagnostic use in a wide range of disease spaces, including undiagnosed genetic disorders, solid tumor research, and hematologic malignancies. Recently, Saphyr has been used to publish research on acute myeloid leukemia, non-small-cell lung cancer, and several microdeletion and microduplication syndromes.
In addition to disease research, Saphyr can be used for gene discovery, genome instability detection, genetic engineering research, evolutionary biology, and reference genome assembly. A full list of publications utilizing Saphyr can be found on our website under publications.
OSP: How do you expect/hope this tool will benefit patients, research, caregivers and other stakeholders in the short- and long-term future?
EH: We expect Saphyr to become a primary tool for research into a variety of genetic diseases and cancer resulting in the discovery of new therapies for these patient populations. Specifically for COVID-19 research efforts, we hope that whole genome analysis studies help identify new therapeutic targets or strategies to better help patients before they become critically ill.
We also expect that clinicians will continue to adopt the Saphyr system for the clinical diagnosis of genetic disease and cancer, to optimize and simplify the clinical workflow and increase the diagnostic yield compared to the current standard of care.
OSP: Do you have anything to add that we didn’t touch upon?
EH: Even today we find that many people don't realize how important characterizing SVs are when doing whole genome analysis. Doing whole genome analysis without looking at SVs is a bit like trying to put together a puzzle that doesn’t have all the pieces – you're never going to get a complete picture; that level of analysis just won't suffice anymore.
When it comes to something like understanding how genetics affects COVID-19 disease severity or which treatments are most effective for a leukemia patient, we really need researchers to have the most complete picture possible.