“High risk” cell populations may be playing important roles in human disorders and diseases
Research in the University of Utah Gregg Lab is focused on understanding genetic and epigenetic pathways and neuronal circuits that influence motivated behaviors and susceptibility to mental illness.
Mental illnesses are extremely complex and involve both genetic and environmental factors that alter brain functions and behavioral drives.
The NIMH estimates that about one in four Americans suffer from a diagnosable mental disorder with nearly 6% suffering serious disabilities as a result, and that the total cost of serious mental illness in the US exceeds $317 billion per year.
In the first half of the twentieth century, developmental biology and genetics were separate disciplines
Epigenetics attempts to provide new insights into the mechanisms for unfolding the genetic program for development.
The word epigenetics was coined by Waddington to link developmental biology and genetics. Epigenetics could be broadly defined as the sum of all those mechanisms necessary for the unfolding of the genetic programme for development. Several decades later specific mechanisms were proposed in which information was superimposed on DNA sequences. In particular, it was suggested that 5-methyl cytosine had a role in controlling gene expression, and also that the pattern of methylation was heritable. These predictions are now supported by a large body of evidence which shows that methylation is strongly associated with gene silencing in a variety of biological contexts. There are now also many examples of epigenetic inheritance through the germ line There are several other important epigenetic mechanisms involving chromatin and histone modifications, and also the expanding field of regulatory RNAs. The human epigenome project will unravel the pattern of DNA methylation in different tissues, and will this determine whether the regulation of gene expression is at the level of DNA or chromatin, or both.
Continue reading Epigenetics: a Historical Overview, Taylor and Francis, doi.org/10.4161/epi.1.2.2762, 2006.
Gene editing might also be used, in principle, to make genetic alterations in gametes or embryos, which will be carried by all of the cells of a resulting child and will be passed on to subsequent generations as part of the human gene pool. Examples that have been proposed range from avoidance of severe inherited diseases to ‘enhancement’ of human capabilities. Such modifications of human genomes might include the introduction of naturally occurring variants or totally novel genetic changes thought to be beneficial.
Germline editing poses many important issues, including:
the risks of inaccurate editing (such as off-target mutations) and incomplete editing of the cells of early-stage embryos (mosaicism);
the difficulty of predicting harmful effects that genetic changes may have under the wide range of circumstances experienced by the human population, including interactions with other genetic variants and with the environment;
the obligation to consider implications for both the individual and the future generations who will carry the genetic alterations;
the fact that, once introduced into the human population, genetic alterations would be difficult to remove and would not remain within any single community or country;
the possibility that permanent genetic ‘enhancements’ to subsets of the population could exacerbate social inequities or be used coercively;
and the moral and ethical considerations in purposefully altering human evolution using this technology.
It would be irresponsible to proceed with any clinical use of germline editing unless and until
the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives,
and there is broad societal consensus about the appropriateness of the proposed application.
Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.
Scientists debate ethics of human gene editing at international summit
A major component of the National Academy of Sciences and the National Academy of Medicine’s Human Gene-Editing Initiative is an international summit to take place December 1-3 in Washington, D.C. Co-hosted with the Chinese Academy of Sciences and the U.K.’s Royal Society, the summit will convene experts from around the world to discuss the scientific, ethical, and governance issues associated with human gene-editing research.
Genes and the wider environment are inextricably intertwined, each affecting the other
Evidence has been mounting about the importance of interactions between people’s genetics and their environment, especially in pregnancy and childhood. Knowledge about how wider environmental factors can turn genes on and off—the new science of environmental epigenomics—is gaining wider coverage and influence. Research has shown that genes and the wider environment are inextricably intertwined, each affecting the other. These gene markers can be passed on to future generations in mammals, and they can also be reversed.
Continue reading Children are the guardians of our genome, thebmj, 2015;351:h6265, 23 November 2015.
Scientists developing model that predicts drug side effects in different patients
2015 Study Summary
Understanding individual variation is fundamental to personalized medicine. Yet interpreting complex phenotype data, such as multi-compartment metabolomic profiles, in the context of genotype data for an individual is complicated by interactions within and between cells and remains an unresolved challenge. Here, we constructed multi-omic, data-driven, personalized whole-cell kinetic models of erythrocyte metabolism for 24 healthy individuals based on fasting-state plasma and erythrocyte metabolomics and whole-genome genotyping. We show that personalized kinetic rate constants, rather than metabolite levels, better represent the genotype. Additionally, changes in erythrocyte dynamics between individuals occur on timescales of circulation, suggesting detected differences play a role in physiology. Finally, we use the models to identify individuals at risk for a drug side effect (ribavirin-induced anemia) and how genetic variation (inosine triphosphatase deficiency) may protect against this side effect. This study demonstrates the feasibility of personalized kinetic models, and we anticipate their use will accelerate discoveries in characterizing individual metabolic variation.
Sources and more information
Personalized Whole-Cell Kinetic Models of Metabolism for Discovery in Genomics and Pharmacodynamics, sciencedirect, doi:10.1016/j.cels.2015.10.003, 28 October 2015.
Researchers are on their way to predicting what side effects you’ll experience from a drug, University of California, November 2, 2015.
Scientists developing model that predicts drug side effects in different patients, medicalnewstoday, 3 November 2015.
Are we reaching an inflection point toward precision medicine?
Each year at the annual American Society of Human Genetics (ASHG) meeting I follow certain rituals. During the first “poster session”, I quickly peruse all of the vendor booths on the floor to assess something of the overall flavor of the commercial space’s focus. During the next two poster sessions I cruise all of the aisles of the scientific posters and scan the titles. This is sort of a daunting challenge requiring months of aerobic training as the number of posters presented at ASHG is huge -more than 3,000 this year. From this, I gain some insights on where genomic science is focused. I find that this ritual provides a valuable overall snapshot of the state of the field of human genetics. Over two decades of watching, broad trends have included linkage studies for gene discovery using microsatellites, mapping of the anatomy of the genome, cataloging of human genetic variation, SNP genotyping/genome wide association studies, and the explosion in sequencing technologies.
This year, at least by my eye, there was a qualitative difference in both the commercial and scientific offerings. ASHG, which has typically focused on discovery science, had much more of a feel of clinical application. Numerous vendors from academic and private industry were promoting clinical sequencing services, microarray technologies, and health informatics software relevant to managing genomics data. Posters covered a very wide spectrum of topics but many dealt either with interrogating clinical data for genomic discovery or the clinical application of genomic technology in the context of ongoing health care delivery. In short, ASHG had the feel that the genomics community has reached an inflection point in the trajectory towards a vision of precision medicine.
There are several underlying factors that could have facilitated this sea change. First, inexpensive genotyping and sequencing have made studies of genotype/phenotype correlations accessible to the scientific masses. Second, health informatics systems have matured to the point (I say this with some hesitation as at least my home institution’s electronic health record [EHR] system is hardly as mature as I would like it to be) that useful information might be gleaned from EHRs about large numbers of properly consented individuals. Finally, and I think most importantly, the climate of fear regarding the integration of genomic discovery research into mainstream clinical care has abated. The center of gravity of discussions around genomics ethical, legal, and social issues has shifted from “Should the genomics research enterprise integrate with clinical care?” to “How can genomics research synergize with clinical care to benefit the widest population possible while minimizing harm?” Also, it seems that the boundaries of public tolerance for personal information sharing in electronic media have changed largely because of the penetration of social media in society. Additionally, at least in the U.S., there seems to be a strong trend towards interest in learning about personal determinants of health (think fitness trackers that follow your every move) that is likely benefiting genomics research participation.
More directly, programs like the National Human Genome Research Institute’s eMERGE, CSER and IGNITE have funded projects that are informing the field with preliminary data across a variety of domains relevant to a future where medicine becomes more individualized. On the regulatory front, the FDA has embarked on a new initiative to overhaul processes for evaluating genomic technologies. Several large health systems, such Geisinger and Kaiser have invested heavily in population scale sequencing initiatives to learn how such information might be used to improve the well-being of their customers. Finally, the announcement regarding NIH’s Precision Medicine Initiative seems to have crystallized the realization across academic health systems that genomics is about to come to main street, and not just to a few enclaves of genomics expertise. Genomics has a long way to go on the trajectory towards application in population health, however these projects are helping to tackle some of the more challenging issues facing the integration of genomics into mainstream clinical care.
Remarkable as this sea change is, it is incumbent on those of us at the interface of public health, health care, and genomics to continue to demand that the genomics community not lose the trees for the forest. In order to benefit the widest number of individuals possible, precision medicine must be predicated on a firm foundation of evidence of health benefit for each application and intended use.
Personalized or precision medicine maintains that medical care and public health will be radically transformed by prevention and treatment programs more closely targeted to the individual patient. These interventions will be developed by sequencing more genomes, creating bigger biobanks, and linking biological information to health data in electronic medical records (EMRs) or obtained by monitoring technologies. Yet the assumptions underpinning personalized medicine have largely escaped questioning.