More than Halfway There: Richard Gibbs Talks Clinical Genetics with Mendelspod
Wednesday, November 9, 2016
Many scientists who participated in the original Human Genome Project shared a grand vision that individual genomes would one day be part of routine medical care. Genomics veteran Richard Gibbs, founder and Director of the Genome Sequencing Center at Baylor College of Medicine, tells Mendelspod host Theral Timpson in a new podcast interview that “we are more than halfway [there].”
In the podcast, Gibbs shares his perspective on the complementary roles that genomics and genetics approaches have in driving our understanding of human biology. He noted that long before the Human Genome Project gained momentum, the discovery of human single gene defects in pediatric disease “had been long regarded as a very good way to advance biology and to advance knowledge.” The study of Mendelian disease is not only of tremendous benefit to patients and their families, but it is a powerful empirical approach to advancing biological understanding. However, the Human Genome Project marked the beginning of efforts to develop a complementary, more systematic approach to genomics. He notes that, “there really was this departure between human genetics and genomics for a decade and a half or more, really because of the demands of doing the genome project there was too much to do to stop and think about some of these more fundamental problems in genetics.”
Gibbs observes that we have now entered a new chapter, where we are closing the loop and marrying the tools and methods developed to sequence and study the human genome with the single-gene approach to unraveling complex systems. In recognition of the importance of single-gene diseases, six years ago the US government created a national program to centralize, streamline, and accelerate the study of Mendelian disease with the establishment of Centers for Mendelian Genomics at the Baylor College of Medicine and several other sites. Gibbs notes that at Baylor, they are combining the knowledge, resources, and tools developed during the Human Genome Project with their longstanding role as a leader in hospital and patient care services, not only helping families but hopefully generating insights into a wide range of common diseases which share phenotypes with single-gene disorders.
Gibbs explained that currently, from a cohort of unscreened, unselected patients suspected of having a disorder caused by a single gene defect, only 25-28% can be diagnosed with a known Mendelian disease. The mainstay diagnostic tool they use at the Baylor Center for Mendelian Disease is whole exome sequencing (WES), but given the low solve rate, one of their goals is to learn how they can supplement WES with new technologies and methods to arrive at what he calls the “best quality genome”. He states that long-read sequencing will have a role to play in this, noting that with PacBio sequencing systems, “we can resolve parts of the genome that are difficult otherwise,” and that for at least small number of genomes, we need “the best amount of information we can possibly get.” One idea he has for a supplementary method is a SMRT Sequencing test to examine short tandem repeats, which can cause disease when expanded, such as in Fragile X syndrome and various ataxias. Such a test would “take all of the regions in the human genome which are known to cause a disease phenotype in an expanded state, and … test for them in a single test or method – enrich for flanking regions, then sequence through the long repeats.” They are also exploring questions such as, “Can we use PacBio [sequencing] to revisit cases where we don’t yet have an answer from short read methods?” and “Can we benefit from taking a small fraction of the samples and adding in long reads to improve haplotype descriptions, then use that information across the whole study?” The key to making progress, according to Gibbs, is to “keep your eye on the ball – the quality of the genome product – rather than focusing on any one method of getting there.”
Towards the end of the interview, Gibbs shares his assessment of our progress towards integrating genomics and medicine. From Gibbs’ perspective, the biggest obstacle to moving genomics fully into the clinic is a more complete deciphering of the genome and better understanding all the allelic contributions to complex disease. “You can’t take your sequencing to the doctor’s office right now as an adult” and expect them to tell you about your future risks for common diseases, he says. “We just in general don’t have that information.” That said, Gibbs argues that “by many criteria, what we see in front of us today is just mind-blowing and represents an enormity of progress.” He is particularly heartened by the evolution in how medical research is now being conducted, which he attributes in part to the increasing incorporation of the science of genomics into medicine. “If you look at the state of medicine today, and the more scientific nature of many of the investigations in clinical science, they’re more digital, they’re more genomic, they’re more focused on comprehensive experiments,” Gibbs explains. “We are seeing an enormity of change in many arenas, culturally, knowledge-based, and now at last somewhat in therapeutics.” Overall, Gibbs concludes “things are going pretty well in my view, and although we don’t have a pill for everything, we are really on the right trajectory,” he says.