"Anyway, I keep picturing all these little kids playing some game in this big field of rye and all. Thousands of little kids, and nobody's around – nobody big, I mean – except me. And I'm standing on the edge of some crazy cliff. What I have to do, I have to catch everybody if they start to go over the cliff – I mean if they're running and they don't look where they're going I have to come out from somewhere and catch them. That's all I'd do all day. I'd just be the catcher in the rye and all. I know it's crazy, but that's the only thing I'd really like to be. I know it's crazy."
- Holden Caulfied; The Catcher in the Rye
Talk of genomics is everywhere. It dominates headlines; not just medical, genetics, and tech journals as once was the case. Genomics is truly going mainstream. In a survey conducted by the Genetic Alliance in 2015, a vast majority of respondents report both knowing of genomics and state their belief that it has the capacity to impact health...not just any health...their health and that of family members.
Yet, with all the promise which genomics holds, it is, proverbially speaking, in its teen years and experiencing, like any teen, growing pains and a search for identity, much the same as J.D. Salinger's beloved, narcissistic, and befuddled protagonist Holden Caulfield.
One facet of Genomic Medicine as a whole has a great deal going for it. Sequencing technology. It exists and has proven itself far beyond any further need of proof-of-concept. Unlike other recent 'breakthrough' medical technologies - immunotherapy; still struggling to gain its footing, stem cells: yet to find widespread general clinical applications, gene therapy: still in a 20-year recovery process from the abysmal failure of its first incarnation, the much vaunted CRISPR which, though incredibly promising, still must undergo lengthy and comprehensive human clinical trials, and Precision Medicine which will entail enormous funding, infrastructure, and political determination - genome sequencing is here and ready to go.
Even so, a myriad of issues remain. Privacy. Data sharing. Incidental findings. The "big data bottleneck." The current prohibitive price which hinders widespread use. Lack of widespread insurance coverage. The fact that genomics really exists as an entity in the modern, industrialized world. Are we ready for the Seven Billion Genomes, that is, the sequencing of every man, woman and child on earth? Clearly not. Only a very few nations currently have large sequencing programs, and these undertakings are mostly limited in scope to identifying rare, exceptional cases of genetic disease and cancer. General sequencing continues to provide diagnoses and identify previously unknown variants at a nice pace, but achieving killer-app status will probably take another decade.
So genomics' identity, at least for the foreseeable future? Mass-screening? Clearly not. As the basis for Precision Medicine? Not yet. Matching best, individualized treatment with a person's DNA profile is in its infancy. Realization of this "ideal" will take massive political will as well as probably the largest financial outlay in the history of Medicine. Replacing traditional newborn screening, the Guthrie, heel-prick, blood spot assay - one of the most successful programs in the history of Public Health - with genomic-based screening? Experts agree this will not be the case in the foreseeable future; many ethical considerations need to be addressed.
It would seem that any widespread breakthrough utilization of genomics is beyond the horizon; a shining beacon for the future. All 'killer-apps' are on the proverbial 'batters'-deck.' Except for one...
It is one of the most impactful statistics in the Rare Disease World - 30% of children with rare genetic disorders will not live to see their fifth birthday. It is also a fact that approximately 3% of newborns admitted to neonatal intensive-care units - many of whom have undiagnosed genetic disorders - do not survive. Salinger's protagonist Holden Caulfied alludes to children going over the cliff - clearly in the context of genetic disorders, the steep, unforgiving cliff is most prominent in the first days and years of life, a time when accurate diagnosis of an underlying disorder is critical.
Several extremely intriguing pilot studies have been undertaken to assess the efficacy of genome sequencing in the NICU, not the least of which is that conducted by Kansas City's Children's Mercy Hospital, the full results of which were published in 2015 in the journal Lancet Respiratory. Highlights of the study include: 1) the STAT-Seq test helped diagnose a genetic disease in more than one half of 35 critically ill infants tested, compared to just nine percent with standard genetic tests; 2) As a result of receiving a specific disease diagnosis, clinical care was refined in 62 percent of infants, including 19 percent who had a markedly favorable change in treatment. In the "Rare World" these results can and should be considered nothing less that ground-breaking. And as the "big data" compilation of DNA biomarkers expands, one can imagine the rates of diagnosis increasing markedly.
What would it take for the methods of this pilot study - rapid, 26-hour sequencing and diagnostic turnaround - to become a widespread practice? A sequencer in every hospital? Hardly. It would, theoretically entail a network of regional sequencing centers by which messengers could easily, geographically access regional diagnostic hubs. A center or two in each US state. A center, two or, perhaps a few more, depending on size, in each country. In many cases, such 'hub" centers for sequencing and interpretation exist - integrating the STAT-Seq 26-hour technology, or any faster system which might supplant it, would be the primary challenge. A sick newborn with a mysterious disorder precariously balanced between life and death? Not hard to imagine the voice of an attending physician of hospital director ringing out clearly...Sequence It! Blood is drawn, a messenger rushes the sample to the sequencing center in a large hospital 2 hours away, and the next day a definitive diagnosis upon which attending physicians can act: Pallister Killian Mosaic Syndrome.
Emergency medical genomes as the journal Genome Medicine calls them are the here and now of the promise of Genomic Medicine, and nowhere more than the NICU are they poised to immediately "disrupt" the status-quo. Testing of critiically-ill newborns is wrought with none of the concerns of mass-sequencing. Consent goes out the window, The issue of incidental findings is a moot point. Financial cost need only be measured in the price of saving a tiny life. The mission is to preserve and potentially save life...STAT!
In the coming years, many countries will contemplate commencing Genomics and Precision Medicine programs of their own. Cost, efficacy, and perceived benefits will be major issues of debate and discussion, Were I a member of a scientific advisory board going before medical and financial committees stating the case, you bet I would present, first and foremost, the Children's Mercy study. Genomics, I believe, needs a great "sales-pitch," and saving critically-ill newborns is as noble, dramatic, and heartening as it gets.
Genomics has its killer-app. Its implementation would not be difficult. It would take planning, coordination and not that much more. As Holden Caulfield could not have imagined, it has the potential to become the Genomic Catcher in the Rare Disease Rye.