Make Db Human Characters Great Again
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Good afternoon. As president of the American Society of Homo Genetics (ASHG), it is my pleasure and privilege to welcome you to the 66th annual meeting of our society. It is a particular joy to join you in this beautiful venue in the spectacular metropolis of Vancouver. This eighth visit of ASHG to the great country of Canada marks a especially of import fourth dimension to acknowledge and applaud the essential contributions of our international colleagues to the vibrancy and relevance of our gild. In broader terms, the ability of human genetics every bit a discipline to deliver on the hope of improving wellness and wellbeing worldwide in an equitable, just, and sustainable manner will crave an unwavering commitment to collaboration, respect, and cultural sensitivity within our community. In this spirit of tearing downwardly all walls, it is a distinct pleasance to welcome scientific and medical colleagues and trainees from over 66 countries to this meeting. I strongly encourage anybody from everywhere, but particularly the young people, to gather often in large and unruly groups to gloat diversity and conspire to practice great things together.
In keeping with this middle to the futurity, the themes of collaboration and mentorship will be emphasized throughout this coming together. Elaine Zackai will be the recipient of the countdown ASHG Mentorship Laurels. I could non imagine a more worthy choice than a consummate clinician educator who integrates the bones and clinical sciences to serve and inspire her patients and trainees alike. In the Presidential Symposium, titled "Mentoring in a Challenging Environment," Huda Zoghbi, Lon Cardon, and Kym Cold-shoulder will share their perspectives regarding what information technology will take to gear up the next generation of man geneticists tasked with realization of the full potential of precision medicine.
In partnership with the European Society of Man Genetics, a articulation Building Bridges session volition address navigation of career paths in human genetics. Nether the expert guidance of Chair Tony Antonellis, this year'southward ASHG Programme Committee has fashioned an agenda that is both innovative and responsive, including implementation of specific recommendations of a task strength requested by ASHG membership, convened past the ASHG Board, and led by Dian Donnai to heighten the integration and presentation of clinical content at our annual coming together.
Every bit yous will hear about in greater item at the business meeting on Friday, our order remains financially sound, strategically engaged, and broadly relevant. In recognition of the leadership position of our guild worldwide and the increased complication of policy issues related to the evolution and application of genetic technologies, the sharing of genetic data, and the protection of genetic privacy and against genetic discrimination, the ASHG Lath established the position of Managing director of Science Policy and recruited Derek Scholes, a graduate of our joint policy fellowship with the National Human Genome Research Institute, to help shape the policy platform and craft the public voice of ASHG. Over the past twelvemonth, the opinions of our membership take been heard on many issues, including germline gene editing, the Genetic Research Privacy Protection Act, the Canadian Genetic Non-Discrimination Act, FDA oversight of side by side-generation-sequencing-based diagnostic testing, and expansion of NIH funding, to name a few. ASHG has expanded its reach with regard to the educational activity of non-genetic healthcare professionals, including the development of teaching programs and tools, the formation of strategic relationships with academic, industrial, and institutional partners, and the launch of the Genomic Medicine Education Consortium to fund educational initiatives and ensure the vitality of the ASHG mission over the long term. ASHG leadership continues to explore mechanisms to enhance the multifariousness of and improve serve our membership. A recent example is the expanded function of trainees in the concern of our society, including full voting representation on the board and inclusion on nigh every ASHG committee. Our communications office seeks to attain out to members in new and creative ways that maximize appointment, advisory content, and discourse. Equally always, we welcome your input and ideas both at the business concern meeting and at ASHG Adjacent, a strategic planning session where members and society leadership volition review progress on the 2013 strategic plan and consider new priorities and initiatives.
All right, with that out of the way, let'south address the 900 lb gorilla in the room—that unfortunate title, "Let's Brand Human being Genetics Great (Again): The Importance of Beauty in Science." Outset lesson for time to come ASHG presidents: keep your wits about you when you get the email from ASHG staff stating that the program goes to press in 10 min and that they actually demand the title now. Second lesson: humor in agony rarely works. In all fairness, there is an embedded bulletin that I feel strongly about. Human being genetics has consistently remained a groovy, highly innovative and broadly impactful discipline since its inception, variably placed at somewhere between the last 60 and 150 years, depending on your perspective. This has been accomplished past consistently ascent to the occasion—by pulling the proverbial theoretical or technological rabbit trick when the field was stalled or the way frontward was less clear. I would argue that human genetics remains great today by virtue of our communal ingenuity, productivity, and resolve.
I might also argue that in that location is a piddling more introspection and a little less swagger in our field at the moment as a result of both external criticism and internal ambiguity; in essence, it's once more fourth dimension to piece of work our magic.
I tin vividly remember the outset ASHG meeting that I attended. It took identify in my home city of Baltimore in 1989. The air was thick with excitement sparked by the recent success of positional cloning in humans, exemplified by the identification of the cystic fibrosis gene.1 To a pediatric cardiologist in training with a recent commitment to improve understanding and serving people with Marfan syndrome, the allure was undeniable. Amazingly, these scientists (read alchemists) could use tractable methods to accomplish a definitive foothold in the pathogenic sequence for a previously mysterious disorder. Analogous to the evolution of the inexplicably powerful methods of quantum mechanics in the early 20thursday century, these theoretical and technical advances in genetics set the stage for even novices in the field to brand meaningful contributions—my kind of place, I reasoned.
An immersion in the history of genetics revealed to the impressionable me, and to the jaded me fifty-fifty now, a sense of dazzler in science that I had not experienced since junior loftier physics. The simplicity of Newton'south laws, Mendeleev's organisation of the periodic table of elements, or Bohr'southward model of the hydrogen cantlet made their power to reconcile or even predict experimental observations, such as the motions of the planets or chemical properties of imaginary substances yet to be observed, all the more astounding. To fully appreciate that, when combined, the audacious deductions of Darwin and the rigor of Mendel established the foundation for full conceptualization of modern biologic reasoning was equally inspiring.
To learn that both weathered criticism in their time—Mendel by the proffer that he additionally study hawkweed before making too much of a fuss out of his pea experiments and Darwin by the likes of Lord Kelvin, the greatest natural philosopher of his age, who was equally slap-up at underestimating the age of the earth and hence the plausibility of natural selection—made me cheer.2 The prescient sentence in Watson and Crick'south one-folio paper describing the structure of Deoxyribonucleic acid, "It has not escaped our notice that the specific pairing we accept postulated immediately suggests a possible copying machinery for the genetic textile," made me laugh out loud.3 Together, this judgement and the opening comments substantially dismissing structures proposed by Pauling or Fraser created a sense of something uniquely beautiful, a sense of triumph complete. Considered in the context of Rosalind Franklin's critical contributions, this makes my 20th century scientific all-star listing, which likewise includes Einstein's full general relativity, Dirac'south electron equation, Brenner and Crick's frameshift experiments defining the triplet nature of the genetic code, and their independent intuition regarding the essential beingness of messenger and transfer RNA. Honestly, if I were fully aware at the age of 13, my bedroom wall would accept included posters of Mickey Pall, Angie Dickinson (as a policewoman), and Sydney Brenner. Strange, but true.
Looking back, I am awed past the advances made in our field over the past 25 years, their impact on biology and medicine, and the general character of their practitioners. I am immensely grateful for the welcome that I received by colleagues at Hopkins, including Victor McKusick, Haig Kazazian, David Valle, Clair Francomano, and Reed Pyeritz, and for the sustained mentorship and friendship afforded past others, notably Barbara Migeon, Aravinda Chakravarti, Gary Cutting, Peter Byers, and Francesco Ramirez. From my first ASHG meeting or Annual Short Form on Medical and Experimental Mammalian Genetics, the firsthand sense, the prevailing sense in our field, was one of both unprecedented opportunity and unavoidable obligation. We tin can and will revolutionize biology and medicine. At that place is work to do. Let's do it together. Get to work.
Swell work was done, and beauty was apparent. Mysteries of inheritance were decorated with names and mechanisms such as mosaicism, imprinting, apprehension, or copy-number variation. Mendelian disease genes came in a trickle—and then a torrent—ofttimes informing the diagnosis and occasionally the management of rare conditions or even more mutual just complex presentations of component phenotypes such as atherosclerosis, arrhythmia, or seizures. Nosotros learned to look the unexpected, including the realization that our gut flora deserves an opinion, that in that location is such a thing every bit too clean, and developmental disability can exist reversible. Reproductive options were greatly expanded, and reproductive outcomes improved. Nosotros learned about who we are and how we got hither, both figuratively and literally.
Perchance our accomplishments over the final few decades will exist all-time remembered, and nigh favorably judged, by the remarkable ability of our technological advances to meet and exceed our insatiable cry for more—more than polymorphic markers with more inherent informativeness; markers with less informativeness but many more of them; more sequence; more sequence for more than species; more sequencing chapters; more coverage of the exome; more than the exome; more sample size; more cohorts; more than powerful belittling methods; more reference databases.
On this 18thursday day of Oct, 2016, I am pleased to announce that nosotros accept more than—and it is skillful. But there is more work to do. Let's do it together.
In assessing our progress and prospects, I found information technology quite revealing to review the presidential addresses of iii pioneers in our field—three early thought leaders and three of my heroes: Victor McKusick, Barton Childs, and Arno Motulsky.4 , 5 , 6 All three predicted the so-called "medicalization" of human genetics as both inevitable and a virtue. In 1974, Victor noted that "medicine has given focus, direction, and purpose to human genetics" and that "this synchronization has occurred … without whatever weakening, indeed with strengthening, of the basic scientific discipline foundations of the field." To the list of fundamental questions upon which the do of medicine is based—what is wrong (diagnosis), what is going to happen (prognosis), and what can be done about it (treatment)?—he added, why did information technology happen? The answer to this paramount question in our field is the footing of "both prevention and scientific progress." He stated that "if expression of a mutant gene were quantitatively and qualitatively identical in all cases, medical genetics would, relatively speaking, exist child'south play. Learning medicine … is largely a matter of learning how to cope with the variability in the clinical effects of given etiologic agents."4
In 1976, Barton divers affliction as "a state of individual homeostatic abnormality." He argued that "such a definition places illness squarely where it should exist—in an evolutionary and social context." This "view of disease as an aberration of adaptation in the face of conditions which are suboptimal, not necessarily for all, only for [at least] ane genetically and socially singled-out individual" highlights the shortcomings of a purely statistical standpoint and offers the potential to "transcend the conventional restrictive concept of etiology."5 Barton'south address was a tough but highly memorable read with a density of ideas that was admirably matched by clarity of thought. It was with both joy and remorse that I remembered him at every morning report and case briefing during my pediatric residency request, "Why is this patient with this disease presenting with this problem at this time?" The joy relates to my current admiration for his insight and persistence; the regret—to the shrugs and (united nations)knowing glances shared by me and my beau trainees in the face of slumber deprivation and the pressing need to catalog lab results and write discharge summaries.
In 1977, Arno contended that "in view of the complexity of genetic and environmental factors involved, a Mendelian approach which attempts to isolate individual factor activity in the multifactorial common diseases and normal behavioral traits is simplistic." To an extent, he argues, prevailing practices were related to the pragmatic pick of scientists to address "nontrivial problems [that could] exist solved past existing concepts and methods." In essence, if biochemistry is the "fine art of the soluble," then human genetics is the art of the statistically tractable. Despite such limitations, Arno counseled that "spectacular" results in etiologic understanding could exist achieved when human genetic observations were combined with those of other fundamental basic sciences, for which he cited the synergistic contributions of McKusick and Neufeld in unraveling the mucopolysaccharidoses as an example.6 What Victor and Barton and Arno were telling usa, and what others since take echoed, is that information technology is really complicated, that the devil is in the details, and that our field avoids the tenet that biochemistry or biology (of the prison cell or developmental types) should exist on at least equal footing with Bonferroni at its peril.
I have besides given all-encompassing consideration to the needs and wisdom of my patients with a genetic predisposition for affliction. When we first identified that mutations in the gene encoding fibrillin-one cause Marfan syndrome, a multisystem connective tissue disorder associated with skeletal deformity, ocular affliction, and a astringent risk of early on death due to aortic root enlargement and rupture, nosotros anticipated that the uptake for prenatal or preimplantation genetic diagnosis would be high. As information technology turned out, even so, many patients were clashing or fifty-fifty strongly disinterested. To an extent, this was most likely related to improved medical and surgical management of the cardiovascular manifestations of this condition. Tellingly, the greatest enthusiasm for assisted reproduction to avoid Marfan syndrome in hereafter generations came from individuals with the most severe features that had the greatest potential to negatively influence their quality of life, such as those in the skeletal and ocular systems, only not necessarily longevity, such as those in the cardiovascular system.
Early in my career, I can retrieve meeting with the parents of a newborn son named Monty, who was diagnosed with the virtually severe and rapidly progressive form of Marfan syndrome, typically associated with death due to congestive heart failure within the first year of life. In dissimilarity to my expectation, the conversation focused on the prospect of relatively pocket-size merely cumulatively important triumphs: might he live long plenty to know his sisters, graduate kindergarten, kick a soccer ball? Although this could accept been attributed to being overwhelmed or naive, this tone, this sense of pragmatic compromise, this satisfaction with minor miracles was maintained throughout Monty'due south overtly challenged notwithstanding unexpectedly long and wholly wonderful childhood.
As a member of the Professional Advisory Board of the Marfan Foundation for the past 25 years, I was initially perplexed but am now inspired by the telephone call of our constituency to requite higher funding priority to research focused on mitigating pes pain or headache frequency or fatigue or social stigmatization. In essence, they asked, can you lot aid u.s. live better with our condition—to more robustly marshal our predetermined genetic allocation with the conditions with which we live? To a meaningful extent, such issues have remained in the exclusive purview of our medical subspecialty colleagues. Tin can and should human genetics have more to say on this matter? Extending across diagnosis, prognosis, or prevention gets usa dorsum to McKusick's fourth question (why did this happen?), to Child'due south query (why to this [simply not that] person, and why now?), and to Arno'due south counsel (understand "the fundamental science base of operations of these conditions"half-dozen). Beyond variants that are benign or pathogenic, they would argue that we need to admit and master "variants of variable significance," because therein lies our leverage.
The two obvious factors to consider are environmental and genetic modification of phenotypic expression of a predisposing genotype. Although both are as formidable bug to address, nosotros have had much more than success with the erstwhile than the latter. Examples include factor-surround interaction in obesity, susceptibility to infection, asthma, allergy, psychiatric disease, and cancer. Success in elucidating such interactions might be informed by consideration of disease in an evolutionary context. If we endeavour to reconcile, in environmental terms, the signature for Darwinian selection of alleles with known biochemical or biologic but not phenotypic consequence, insights regarding affliction mechanism and handling in modern times might get apparent. The opposite of this strategy—explaining known disease allele frequencies by inferring interplay betwixt gene part and historic weather condition—has been commonly applied. Cystic fibrosis, diabetes, and sickle jail cell disease come to mind. The same cannot be said for a more nuanced forward arroyo. An illustrative, if not entirely chronologically authentic, example might be the following: (1) Tibetans have a remarkably high frequency of an allele encoding the p.Cys127Ser gain-of-role variant of PHD2. (2) PHD2 degrades HIF, a factor that ordinarily augments erythropoiesis. (3) This allele in Tibetans protects from altitude-induced rise in hematocrit and fetal loss. (four) Therefore, interest of the PHD2-HIF axis should be explored in various presentations of anemia or polycythemia, and its modulation holds promise in the treatment of a diverseness of diseases, including primary hematologic, thrombotic, and ischemic conditions (adjusted from Lorenzo et al.7).
Another underemployed approach is to understand remarkable escape from disease despite overt environmental exposure. Instead of asking, for example, what alleles predispose to blazon II diabetes or smoking-induced lung cancer, the signals might be fewer but stronger, the requisite sample size lower, and the therapeutic relevance more direct if we look for variant enrichment amongst hearty obese or elderly 80-pack-year individuals.
Examples from our ain piece of work have highlighted the potential for serendipity or clinical ascertainment to inform gene-environs interactions and therapeutic opportunities.8 While studying the ability of various classes of antihypertensive agents to alter the aneurysm phenotype in mouse models of Marfan syndrome, we observed that calcium channel blockers unexpectedly led to hyperacute acceleration of aneurysm growth and tear, literally tripling aneurysm size within v weeks and causing expiry due to aortic rupture inside 6 weeks of treatment initiation. Mechanistic label led to appreciation of a pathogenic office for the PLC-IP3-PKC axis and a protective function for the PKC inhibitor enzastaurin in Marfan mice that had—or had not—received calcium channel blockers. A subsequent retrospective analysis of Marfan-afflicted people who were taking calcium channel blockers at the fourth dimension of enrollment in the GenTAC database revealed an odds ratio of aortic autopsy or aortic surgery during the follow-upwards period of 12.v or 5.5, respectively.
More than recently, we focused on the high chance of aortic dissection in Marfan-affected women who choose to become pregnant. Although dissections have historically been attributed to increased hemodynamic stress, it seemed odd that the majority occur within the first few weeks after delivery. This led to the hypothesis that the hormone oxytocin, which peaks at the terminate of pregnancy and is maintained at high levels during breastfeeding, might exist a contributing factor. Informatively, a Marfan syndrome mouse model that shows near-complete death due to aortic rupture in the early postpartum menstruation is largely or completely rescued by avoidance of lactation or administration of an oxytocin receptor blocker, respectively. The lesson, I recall, is that clues and opportunities are all around united states of america but that we demand to engage the expertise and enact the inclination to recognize and exploit them.
The hope of elucidating gene-cistron interactions in efforts to understand the inheritance, pathogenesis, and treatment of disease has been hotly debated. Although the additive effects of the individual influence of variants at ii or more loci have been documented by both modifier and genome-wide clan studies, the mere existence of not-additive synergistic effects—then-called "true" or "physiological" epistasis—in humans remains controversial. Weinreich defined epistasis equally "our surprise at the phenotype when mutations are combined, given the elective mutations' individual effects."9 In view of how many surprises in human phenotypic expression remain unresolved, among which is "missing heritability," the prospect (peradventure inevitability) of human being epistasis should not exist dismissed.
Indeed, given the ubiquitous nature of epistasis in model organisms and the fundamental biological foundations for its existence, the absenteeism of epistasis in humans seems illogical, or at the very least unfair. In the words of Einstein, "the Lord is subtle, but not malicious." I have to acknowledge that in my frustrated attempt to empathise the mathematical nuances brought to touch on this issue, I became obsessed and inordinately distracted with the task of finding an eminently attainable and unequivocal example in the context of human affliction. I thank Andy McCallion for bringing the example of Rotor syndrome, a course of hyperbilirubinemia, to my attention. Rotor syndrome is a true digenic recessive trait, where biallelic loss-of-part mutations at independent loci are required for any evidence of biochemical or clinical expression.ten This seemed like a major triumph at the time; possibly more chiefly, its recognition allowed me to resume work on this address.
Using particularly denoting reasoning and citing low and/or skewed allele frequencies, small issue sizes, linkage disequilibrium, noise, model complexity, and limiting sample size as potential confounding variables, Haley and Hartl fence that failure to detect a signature for so-chosen "statistical epistasis" at the population level does non infer the lack of influence of genotypic context on the individual (i.e., physiologic epistasis).11 , 12 Haley suggests informed candidate-based studies every bit a path forwards. From a patient-centric viewpoint, differentiation between condiment and true epistatic interactions seems unnecessarily contrived. Their fundamental question is whether an actionable aspect of genetic context, given their primary predisposition, can prevent, delay, or in some mode mitigate attainment of a functional threshold for phenotypic expression.
Two particularly beautiful recent examples of accomplishment in homo genetics come up to mind: those of PCSK9 and BCL11A. The PCSK9 story begins with the demonstration of recurrent mutations with the genetic and subsequent biochemical signature of gain of function in familial hypercholesterolemia. It was afterwards shown that common hypomorphic variants and rare or induced loss-of-part alleles in both humans and mice associate with low levels of low-density lipoprotein (LDL) cholesterol and protection from coronary artery disease in the face of overt environmental and/or genetic predisposition. The heartiness and fertility of an individual compound heterozygous for loss-of-function PCSK9 alleles (with LDL cholesterol of fourteen mg/dL) highlighted the safety of therapeutic strategies aimed at antagonizing PCSK9. Subsequent studies have suggested that, no affair what life throws at you lot (Big Macs, predisposing alleles, or both), PCSK9 antagonists hold promise to ameliorate the length and quality of life through prevention (and perhaps even reversal) of atherosclerosis.13
The BCL11A story begins with a quantitative trait locus (QTL) association report to identify genetic determinants of postnatal product of fetal hemoglobin. Although expression of fetal hemoglobin is typically restricted to fetal life, decades of investigation had shown that it could change the severity of diverse hemoglobinopathies, including thalassemias and sickle cell disease. Low expression or loss-of-function alleles of BCL11A associated with persistence of fetal hemoglobin, amelioration of beta-thalassemia, and productive modification of result parameters, including the frequency and severity of pain crunch in sickle cell disease, allowing conceptualization of a mature therapeutic strategy.fourteen
The bottom line in both of these stories is that furnishings of variation at ane locus were both predicted and observed to modify the clinical event of predisposing variation at some other. By mimicking nature's success in the class of pharmacologic agents or maybe genome editing, real progress will be made. Importantly, it took the likes of Hobbs and Orkin, amid others, with diverse expertise and career-long investment in the problem, to fully prosecute early on leads. Given favorable circumstances, it seems possible—even likely—that similar approaches might link QTLs for bone mineral density, oxygen diffusion capacity, or serum creatinine with revolutionary treatments for osteoporosis, emphysema, or skeletal myopathies, respectively, equally only a few examples.
I began by dismissing the faulty proposition that we need to make human genetics slap-up again. Rather, nosotros every bit a guild and we as a community are collectively blest with a diverseness of talents and the inventiveness and resolve to meet all formidable tasks ahead—to brandish our greatness once again. The call for "more" might need to exist supplemented by a quest for better—better cohorts with better capture of granular phenotypic and ecology information that is better tailored to the specific question at manus, too as better integration of the clinical and basic scientific acumen within our discipline and beyond. Nosotros besides need to demand bookish models that foster and reward cross-disciplinary collaborations and funding priorities that equally nurture big science and the adjacent large affair that lingers in the imagination of our extraordinary individual young investigators. I end firm in the conviction that nosotros are stronger together.
Acknowledgments
I am indebted to my family unit for their love and patience, to my mentors for their perseverance, to my patients for their wisdom and grace, and to my students for all of the above.
References
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339082/
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