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Pⁿ Blog
The Pⁿ Blog is a forum for opinions, questions, controversies, and instructive discussions across the field of pathology and its relevant subspecialties.
Friday, April 04, 2014
The kilobuck genome.
When the human genome project announced in 2000 that the 3 billion base pairs of human DNA had been successfully mapped, the thinking was that major breakthroughs in medicine were right in front of us. Surely the cures for Alzheimers, diabetes, all sorts of genetic conditions, and, of course, cancer were just around the corner.  Well, as we now know, not quite.  Clinical advances based on our knowledge of the human genome have been, at best, modest in the last 14 years.   However, we may now be close to an inflection point in our utilization of this knowledge.  The original government-funded Human Genome Project cost 3 billion dollars and took 13 years.  It is now possible, with automated next generation sequencing to sequence an entire human genome for approximately $1000.  At that price, individualized whole genome sequencing becomes a viable clinical tool. 
Needless to say a LOT of venture capital is being thrown in this direction.  Craig Venter, one of the pioneers in the Human Genome Project has started a company known as Human Longevity with the goal of completely sequencing 40,000 human genomes per year.  This capability has considerable promise in a many medical fields.  Fetal testing for genetic anomalies, for example, will be far more sensitive and allow the detection of a virtually endless number of anomalies, rather than a select few of the more common ones, as is now the case.  Genetic components or predispositions will undoubted be found for many currently enigmatic diseases.  Identification of these predispositions will allow for targeted screening and, in many instances, the development of specific therapies. 
There will undoubtedly be major inroads in our understanding of cancer predispositions and targetted screenings in high risk populations.  The benefits to this approach are likely to be enormous.  Many cancers with specific mutations and a relatively stable genome may yield, at least initially, to targetted therapies.  Drugs directed at tumors with specific mutations will have great potential as first line therapies with little or no associated toxicity.  I remain skeptical, however, that targetted genetic therapy is going to result in dramatic long-term cure rates for many cancers, particularly those high-grade tumors with considerable genetic instability and the ability to "work around"  initial genetic road blocks.  GI stromal tumors (GISTs) are a case in point.  These tumors have dramatic initial responses to Gleevec therapy and yet many (most) ultimately acquire the proper mutations for a biochemical "work around" of the Gleevec road block and Gleevec-resistant recurrences develop several years later.  There may well be some biochemical road blocks for which work arounds aren't biologically possible, but cancer is, after all, "chaos" with entropy on its side and to paraphrase Jeff Goldblum in Jurassic Park, "life (even, or perhaps especially, malignant life) will find a way!"
The other looming issue on multiple levels is reimbursement!  Will insurance companies pay for whole genome sequencing?  Will they pay for enhanced screening based on detected predispositions?  Will they pay for the development and utilization of costly drugs to treat rare and in some cases patient-specific diseases?  At the moment reimbursement for molecular/genetic testing is in most cases a "loss leader" in medical centers.  This has the potential to get much worse as the complexity and expense of the testing increases.  Ultimately, market factors (read: patients demanding it), may lead to increased reimbursement in all these arenas, but only time will tell. 
There's no doubt about it.  We live in interesting times.
About the Author

Stacey E. Mills, MD
Stacey E. Mills, MD, a graduate of University of Virginia (UVA) and the UVA Medical Center, has authored nearly 230 articles, 20+ books, atlases and monographs—including the renowned Sternberg's Diagnostic Surgical Pathology. He has been a practicing Professor and Staff Pathologist at UVA for 30+ years and is Director of Surgical Pathology and Cytopathology. His clinical specialty is general surgical pathology with emphasis on neoplasms and neoplasm-like lesions. Dr. Mills is also Editor-in-Chief of The American Journal of Surgical Pathology.