The Human Side of RNA-seq
Washington University Medical Center sits just down the road from Cofactor’s St. Louis headquarters and is home to a story about the power of RNA-seq that is both heartwarming and scientifically encouraging. Lukas Wartman is a WashU physician who helps oversee the cancer genomics program at the Genome Institute. In the early 2000s during medical school, he was diagnosed with the same cancer that he had chosen to focus on in his studies (acute lymphoblastic leukemia, or ALL).
After a second relapse in 2011 and no obvious drug options based on whole exome sequencing, the research team looking at Wartman’s data shifted their focus to RNA-seq results. This expression analysis led them to a dramatically over-expressed gene that was the target of a drug that had never been tried in ALL. As Wartman says in a paper he authored about his own story (“A case of me: clinical cancer sequencing and the future of precision medicine”), “My leukemia cells were massively over expressing wild-type FLT3 […] in short, the [RNA-seq] results uncovered a novel, unexpected target.” Off-label use of the drug bought Wartman time to undergo a stem cell transplant and survive a second relapse – something he notes is generally considered hopeless. Be sure to read his account at the link above for the full story.
This is the point of RNA-seq, and all molecular tools. Research, preclinical validation, clinical trials, all pointing to eventual mainstream therapeutic interventions based on molecular-level detail. The ultimate metric for all of the science is how it changes an individual patient’s trajectory for the better. Wartman’s story is an unusual case, but we can see the promise of precision medicine therein. He had access to tools unavailable to most patients, and he had a cancer that happened to be driven by a target gene with a known drug. The goal, though, is for stories like this to be common in the near future.
Outside of the scientific advances still required to get to truly personalized medicine, there is a human component, as well. Dealing with patients adds layers of complexity to the technical world of molecular diagnostics. For one thing, genetic testing in general comes with numerous ethical considerations. In any genetic test, there is the risk of discovering variants of unknown significance (VUS). It is one thing to file these mutations away for addition to a large database for future study. It is quite another, though, to bring a patient news that variations exist, “but we have no idea if they mean anything or not.” In other cases, variants known to be causative of – or at least associated with – disease states may show up unexpectedly. These bits of information can be a shock to the patient, learning about a situation totally unrelated to the reason they were tested in the first place. This is where caring genetic counselors and clear communication on the part of clinicians before, during and after testing comes into play.
Another point of discussion is the role of the consumer in seeking out and managing their own genetic data. There is the ongoing debate about who owns an individual’s genetic information. Almost across the board, this issue is being resolved, appropriately, in favor of the individual. But clear communication and extensive educational resources are needed to ensure that people can understand the information and apply it where possible. For example, consider an individual trying to wade through her sequencing results and noting the presence of one or more VUS. This may be extremely concerning in the absence of context provided by a genetic counselor.
Regardless, the data belongs with the individual, and people are taking a more active role in their genetic health. Direct to consumer companies like 23andMe are spearheading this movement, letting people spit in a tube and then scroll through their detailed genetic profile at will. On the research side, efforts such as the UK Personal Genome Project are asking people to contribute their genetic information to public databases. Similar projects are underway in the US, where the 2015 Precision Medicine Initiative includes developing a database with at least a million individual profiles. In this way, people – not just patients seeking medical care, but the public at large – can take ownership of their information while contributing to large-scale work that will lead to improvements in medicine for everyone.
Admittedly, the above situations are generally associated with DNA testing more than RNA. However, RNA offers tantalizing possibilities for consumer-facing offerings in the future. As we have discussed here previously, RNA provides real-time insight into cellular function and physiological processes. Raman Talwar, Cofactor Genomics’ Director of Diagnostic Development, envisions a future where extracellular RNA found in blood and other fluids can be used to obtain snapshots into the body’s state at that moment. There is the possibility that individuals could better understand how they respond to different environmental or lifestyle situations. Tracking personal health information has become relatively commonplace today, with fitness bands and related wearables offering instantaneous insight into our physiological responses to various daily events. Existing DNA-testing products add another layer by providing a relatively static baseline of one’s potential health risks. RNA could add yet another layer, something like a molecular-level version of a heart rate monitor that indicates what is going on at the organ or tissue level.
This ideal of an integrated, individualized system that can be used for monitoring, diagnosis and treatment is far down the road. With current molecular technologies we can begin to see the outline of how something like this might work. Wartman and those like him who have benefitted from early version of precision medicine prove that the ideal is possible, at least in some form. The key will be to ensure that communication and education evolve alongside the scientific advances, giving people access to their personal data and providing them clear direction on how to use it.
Cofactor is eager to apply our experience in designing trustworthy, reproducible RNA assays to human health applications. Are you looking to add RNA data to your clinical workflow? Visit our Clinical Assay page to learn more about what we’re developing, and get in touch to see if we can help support your work.