By Allison Proffitt
September 6, 2016 | HUNTSVILLE—David Goldstein kicked off a genomic medicine gathering* in Huntsville, Alabama, last month with a call for precompetitive gene discovery and a new paradigm of disease treatment.
Goldstein, Director of the Institute for Genomic Medicine at Columbia University Medical Center, compared the scale and promise of the discoveries before us to the “golden age of molecular biology.” We only have one chance to systematically relate genomic differences to what we know about us, Goldstein said, and now is that chance.
Yet Goldstein rejected the definition of precision medicine as the practice of matching genetic variants with drugs. That’s a very, very trivial aspect of precision medicine, he insisted. Instead, researchers and physicians should be working to identify causes of disease and develop treatments based on knowledge of the causes.
Goldstein proposed a new genetic drug discovery paradigm: develop appropriate models based on causal mutations, screen to discover mutational effects, test targeted treatment in appropriate genetic subgroup, and assess generalizability.
But to make progress in this new drug discovery, we must share data. “We must stop competing to discover genes,” Goldstein said, and instead focus our work on finding treatments.
WGS vs WES
The HudsonAlpha Institute and its Executive Vice President for Genomic Medicine, Howard Jacob, have a well-documented stance preferring whole genome sequencing (WGS) to whole exome sequencing (WES). In fact Liz Worthey, director for software development and informatics at HudsonAlpha, mentions her conviction in the disclosures before she speaks.
HudsonAlpha’s sequencing lab has sequenced 6,077,812,593,760,510 bases, Shawn Levy reported, at a turnaround time that’s similar to whole exome sequencing. And Worthey argued that genome interpretation is no more difficult than exome interpretation. Whole genome sequencing has a molecular diagnostic rate of 35%, Worthey said, better than WES.
David Bick, medical director at the Smith Family Clinic for Genomic Medicine, works to bring those diagnoses to patients, and he too argues for WGS. The genome is a “much richer place than the reference genome,” he said, encouraging attendees to view the reference genome as “just a convenience.”
Levy, head of the Genomic Services Lab at HudsonAlpha, agreed that relying on the reference genome vastly understates the complexity and promise of the genome. Ultimately we must shift our thinking away from the human genome to a human genome, Levy said. We want representatives of different groups covering the variety and complexity of genomes.
Right now we are very good at interpreting inherited conditions that are fully penetrant, Levy said. But there is so much more we can do to meld deeper genomic data with known biology.
The Physician Perspective
The challenge facing physicians and genetic counselors in particular is to learn how to balance what we know with what we don’t, the value of the knowledge, and how to communicate it all to patients.
In 1961, 90% of doctors preferred not to tell patients of a cancer diagnosis because of all of the unknowns, Levy said. We’re in the same place now with genomics, he believes, but that is quickly changing.
The physicians and counselors at the Genomic Medicine Conference related challenges communicating knowns and unknowns to their peers and patients.
Bruce Korf, director at the Heflin Center for Genomic Sciences at the University of Alabama, Birmingham School of Medicine, is trying to “short circuit the diagnostic odyssey.”
Doctors find unknowns very challenging, Korf said. VUSs—variants of unknown significance—report variants for which we don’t know the importance. “You’d be surprised at how often that subtle point doesn’t come across the clinicians,” he said. “If there’s one thing I want medical students to know, it’s to not misinterpret VUSs. It happens with rather alarming frequency.”
Getting physician buy in is also crucial.
Amalia Issa, Founding Director, Personalized Medicine & Targeted Therapeutics, University of the Sciences in Philadelphia, recounted the history of antiseptics and anesthesia. Both changed the quality of healthcare dramatically, but only one made life easier for the doctors. Anesthesia use was adopted much more quickly because doctors could see how it improved their lives along with their patients’ experiences.
Genomic medicine, Issa challenged, must be made just as convenient.
Sequencing is shifting, said Howard Jacob in his evening keynote address. “The future of sequencing is not research, it’s clinical,” he said. “How do I know that? For the last two quarters Illumina has missed its earnings numbers.”
* 2016 Genomic Medicine Conference, HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, Aug 8-10
Allison Proffitt
September 2, 2016 | HUNTSVILLE—David Goldstein kicked off a genomic medicine gathering* in Huntsville, Alabama, last month with a call for precompetitive gene discovery and a new paradigm of disease treatment.
Goldstein, Director of the Institute for Genomic Medicine at Columbia University Medical Center, compared the scale and promise of the discoveries before us to the “golden age of molecular biology.” We only have one chance to systematically relate genomic differences to what we know about us, Goldstein said, and now is that chance.
Yet Goldstein rejected the definition of precision medicine as the practice of matching genetic variants with drugs. That’s a very, very trivial aspect of precision medicine, he insisted. Instead, researchers and physicians should be working to identify causes of disease and develop treatments based on knowledge of the causes.
Goldstein proposed a new genetic drug discovery paradigm: develop appropriate models based on causal mutations, screen to discover mutational effects, test targeted treatment in appropriate genetic subgroup, and assess generalizability.
But to make progress in this new drug discovery, we must share data. “We must stop competing to discover genes,” Goldstein said, and instead focus our work on finding treatments.
WGS vs WES
The HudsonAlpha Institute and its Executive Vice President for Genomic Medicine, Howard Jacob, have a well-documented stance preferring whole genome sequencing (WGS) to whole exome sequencing (WES). In fact Liz Worthey, director for software development and informatics at HudsonAlpha, mentions her conviction in the disclosures before she speaks.
HudsonAlpha’s sequencing lab has sequenced 6,077,812,593,760,510 bases, Shawn Levy reported, at a turnaround time that’s similar to whole exome sequencing. And Worthey argued that genome interpretation is no more difficult than exome interpretation. Whole genome sequencing has a molecular diagnostic rate of 35%, Worthey said, better than WES.
David Bick, medical director at the Smith Family Clinic for Genomic Medicine, works to bring those diagnoses to patients, and he too argues for WGS. The genome is a “much richer place than the reference genome,” he said, encouraging attendees to view the reference genome as “just a convenience.”
Levy, head of the Genomic Services Lab at HudsonAlpha, agreed that relying on the reference genome vastly understates the complexity and promise of the genome. Ultimately we must shift our thinking away from the human genome to a human genome, Levy said. We want representatives of different groups covering the variety and complexity of genomes.
Right now we are very good at interpreting inherited conditions that are fully penetrant, Levy said. But there is so much more we can do to meld deeper genomic data with known biology.
The Physician Perspective
The challenge facing physicians and genetic counselors in particular is to learn how to balance what we know with what we don’t, the value of the knowledge, and how to communicate it all to patients.
In 1961, 90% of doctors preferred not to tell patients of a cancer diagnosis because of all of the unknowns, Levy said. We’re in the same place now with genomics, he believes, but that is quickly changing.
The physicians and counselors at the Genomic Medicine Conference related challenges communicating knowns and unknowns to their peers and patients.
Bruce Korf, director at the Heflin Center for Genomic Sciences at the University of Alabama, Birmingham School of Medicine, is trying to “short circuit the diagnostic odyssey.”
Doctors find unknowns very challenging, Korf said. VUSs—variants of unknown significance—report variants for which we don’t know the importance. “You’d be surprised at how often that subtle point doesn’t come across the clinicians,” he said. “If there’s one thing I want medical students to know, it’s to not misinterpret VUSs. It happens with rather alarming frequency.”
Getting physician buy in is also crucial.
Amalia Issa, Founding Director, Personalized Medicine & Targeted Therapeutics, University of the Sciences in Philadelphia, recounted the history of antiseptics and anesthesia. Both changed the quality of healthcare dramatically, but only one made life easier for the doctors. Anesthesia use was adopted much more quickly because doctors could see how it improved their lives along with their patients’ experiences.
Genomic medicine, Issa challenged, must be made just as convenient.
Sequencing is shifting, said Howard Jacob in his evening keynote address. “The future of sequencing is not research, it’s clinical,” he said. “How do I know that? For the last two quarters Illumina has missed its earnings numbers.”
* 2016 Genomic Medicine Conference, HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, Aug 8-10
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