Henry T. Greely

Clinical assessment incorporating a personal genome

BACKGROUND The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context. METHODS We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patients full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks. FINDINGS Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported. INTERPRETATION Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients. FUNDING National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Childrens Health; Hewlett Packard Foundation; Breetwor Family Foundation.

A prudent path forward for genomic engineering and germline gene modification

A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed Genome engineering technology offers unparalleled potential for modifying human and nonhuman genomes. In humans, it holds the promise of curing genetic disease, while in other organisms it provides methods to reshape the biosphere for the benefit of the environment and human societies. However, with such enormous opportunities come unknown risks to human health and well-being. In January, a group of interested stakeholders met in Napa, California (1), to discuss the scientific, medical, legal, and ethical implications of these new prospects for genome biology. The goal was to initiate an informed discussion of the uses of genome engineering technology, and to identify those areas where action is essential to prepare for future developments. The meeting identified immediate steps to take toward ensuring that the application of genome engineering technology is performed safely and ethically.

Challenges in the clinical application of whole-genome sequencing

Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine (E A Ashley MRCP, M T Wheeler MD), Department of Medicine (Prof R B Altman MD), Department of Bioengineering (Prof R B Altman), Division of Medical Genetics (Prof L Hudgins MD), Department of Pediatrics (A J Butte MD), and Department of Genetics (T E Klein PhD, K E Ormond MSc, Prof R B Altman), Stanford University School of Medicine, Stanford, CA, USA; and Center for Law and Biosciences, Stanford University School of Law, Stanford, CA, USA (Prof H T Greely JD)

Noninvasive prenatal diagnosis: pregnant women's interest and expected uptake

To investigate pregnant womens level of future interest in noninvasive prenatal diagnosis (NIPD) and what factors might affect expected uptake of this testing.

Detecting individual memories through the neural decoding of memory states and past experience

A wealth of neuroscientific evidence indicates that our brains respond differently to previously encountered than to novel stimuli. There has been an upswell of interest in the prospect that functional MRI (fMRI), when coupled with multivariate data analysis techniques, might allow the presence or absence of individual memories to be detected from brain activity patterns. This could have profound implications for forensic investigations and legal proceedings, and thus the merits and limitations of such an approach are in critical need of empirical evaluation. We conducted two experiments to investigate whether neural signatures of recognition memory can be reliably decoded from fMRI data. In Exp. 1, participants were scanned while making explicit recognition judgments for studied and novel faces. Multivoxel pattern analysis (MVPA) revealed a robust ability to classify whether a given face was subjectively experienced as old or new, as well as whether recognition was accompanied by recollection, strong familiarity, or weak familiarity. Moreover, a participants subjective mnemonic experiences could be reliably decoded even when the classifier was trained on the brain data from other individuals. In contrast, the ability to classify a faces objective old/new status, when holding subjective status constant, was severely limited. This important boundary condition was further evidenced in Exp. 2, which demonstrated that mnemonic decoding is poor when memory is indirectly (implicitly) probed. Thus, although subjective memory states can be decoded quite accurately under controlled experimental conditions, fMRI has uncertain utility for objectively detecting an individuals past experiences.

Broad Consent for Research With Biological Samples: Workshop Conclusions.

Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Centers Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.

What If Extinction Is Not Forever

Although new technologies may make it possible to bring extinct species back to life, there are ethical, legal, and social ramifications to be addressed A 1930s film shows a dog running and jumping inside a fenced enclosure (1)—except that the dog has a strange-shaped head, odd stripes, and a rigid tail that can only move side-to-side. The “dog” is actually one of the last thylacines, a marsupial predator also called the Tasmanian tiger. The film was taken shortly before humans extinguished the species forever. Or did we? Recently, new technologies have made it plausible to try to revive many recently extinct species. Scientists around the world are discussing, and working toward, “de-extinction” (2).

Strangers at the benchside: research ethics consultation.

Institutional ethics consultation services for biomedical scientists have begun to proliferate, especially for clinical researchers. We discuss several models of ethics consultation and describe a team-based approach used at Stanford University in the context of these models. As research ethics consultation services expand, there are many unresolved questions that need to be addressed, including what the scope, composition, and purpose of such services should be, whether core competencies for consultants can and should be defined, and how conflicts of interest should be mitigated. We make preliminary recommendations for the structure and process of research ethics consultation, based on our initial experiences in a pilot program.

The ethics of characterizing difference: guiding principles on using racial categories in human genetics

We are a multidisciplinary group of Stanford faculty who propose ten principles to guide the use of racial and ethnic categories when characterizing group differences in research into human genetic variation.

CRISPR germline engineering—the community speaks

Nature Biotechnology asks selected members of the international community to comment on the ethical issues raised by the prospect of CRISPR-Cas9 engineering of the human germline.