Doris T. Zallen

US gene therapy in crisis

The recent death of a young man, Jesse Gelsinger, in a gene therapy experiment has sent shock waves throughout the US research community. This tragic event has raised new questions about the prospects for human gene therapy. And it has also reopened old controversies about how best to guide the development of this field.

The singular fate of genetics in the history of French biology, 1900–1940

ConclusionIn this study we have examined the reception of Mendelism in France from 1900 to 1940, and the place of some of the extra-Mendelian traditions of research that contributed to the development of genetics in France after World War II. Our major findings are:(1)Mendelism was widely disseminated in France and thoroughly understood by many French biologists from 1900 on. With the notable exception of Lucien Cuénot, however, there were few fundamental contributions to the Mendelian tradition, and virtually none from about 1915 to the midthirties. Prior to 1900, Cuénots work was already marked by a striking interest in physiological mechanisms; his physiological preoccupations played a considerable role in his account of the inheritance of coat color and of susceptibility to tumors in mice. His analysis of the roles of the many genes involved in pigment formation was developed with an eye to one of the first models of the metabolic reactions involved. It yielded one of the earliest suggestions that the steps controlled by single genes involve enzymes as the products of genes.(2)The inflexible structure of the French universities played an important role in discouraging research in genetics and in the failure to train the post-World War I generation in that discipline.(3)During this period the disciplines of physiology, microbiology, and causal embryology were dominant in French experimental biology. The issues that were most prominent within these disciplines—differentiation and development, regulation of growth and morphology, infection and assimilation—were not easily treated within genetics. The failure of Mendelism to resolve a variety of legitimate explanatory issues to the satisfaction of serious investigators trained in the dominant French disciplines also contributed to the failure of Mendelism to penetrate French science. The violent anti-Mendelian polemics put forward by many of the most committed neo-Lamarckians raised many of the same issues regarding the supposed insufficiency of Mendelism. Cuénots reluctance to encourage his students to pursue careers in genetics illustrates the compound nature of the resistance. Despite the absence of a developed tradition of Mendelian research, a French school of molecular genetics had developed by the 1950s. It flourished outside the university system at the Institut Pasteur, the Institut de Biologie physico-chimique, and the CNRS (though some of its leading figures had university connections), and it was only beginning to enter into university curricula. The most important indigenous research that informed the new tradition was that of Eugène Wollman on “paraheredity” of phage infection and lysogeny, of André Lwoff on the physiology and nutritional requirements of protozoa and bacteria, and the embryologically influenced genetic investigations of Boris Ephrussi. The conceptual and methodological resources of the French school were enriched by this background; a full understanding of the products of the fifties, we believe, requires a proper appreciation of these antecedents. Molecular genetics in France grew out of the Pasteurian tradition of microbiology and the highly developed tradition of causal embryology as modified by Ephrussi. Both of these traditions were extra-Mendelian and not anti-Mendelian, but they both shared a number of the problems and assumptions that were at the center of the extremist resistance to Mendelism. In many respects, then, it is more fruitful to see the entry of French biology into molecular genetics as a development of its microbial-physiological and causal-embryological traditions, coopting the tools and techniques of genetics, rather than the other way around.

The Role of the Vilmorin Company in the Promotion and Diffusion of the Experimental Science of Heredity in France, 1840–1920

Institutions in the commercial sector, especially those marketing seeds for agricultural use, have long had an interest in understanding heredity. Much of what we know of this relationship concerns the period since the rediscovery of Mendels work in 1900. Little is known of the nature of this relationship in the nineteenth century. In this paper, we will focus on the role played by one company - the Vilmorin Company in France - in the promotion of an experimental science of heredity from 1840 to 1920.

The EGAPP initiative: Lessons learned

The Evaluation of Genomic Applications in Practice and Prevention Working Group was first convened in 2005 to develop and test evidence-based methods for the evaluation of genomic tests in transition from research to clinical and public health practice. Over the ensuing years, the Working Group has met 26 times, publishing eight recommendation statements, two methods papers, and one outcomes paper, as well as planning and serving as technical experts on numerous associated systematic reviews. Evaluation of Genomic Applications in Practice and Prevention methods have evolved to address implications of the proliferation of genome-wide association studies and are currently expanding to face challenges expected from clinical implementation of whole-genome sequencing tests. In this article, we review the work of the Evaluation of Genomic Applications in Practice and Prevention Working Group over the first 8 years of its existence with an emphasis on lessons learned throughout the process. It is hoped that in addition to the published methods of the Working Group, the lessons we have learned along the way will be informative to others who are producers and consumers of evidence-based guidelines in the field of genomic medicine.Genet Med 2014:16(3):217–224.

Boris Ephrussi and the Synthesis of Genetics and Embryology

The career of Boris Ephrussi (1901–1979) presents a series of fascinating perspectives on the intellectual and sociological difficulties that plagued those who wished to reconcile genetics and embryology during the middle of this century (2–8). Ephrussi was born in a suburb of Moscow, but spent much of his working career in France, with important periods in the United States. He made major contributions to the rapprochement between genetics and developmental biology. His work, which we believe has been undervalued both by historians of biology and by subsequent generations of biologists, is worth studying for at least three reasons: 1. Throughout his long career, he sought an adequate causal analysis of differentiation and development. Relatively early, he saw the need to accomplish this task by uniting the findings of genetics with those of embryology. To this end, he employed a great variety of experimental organisms and techniques and explored numerous conceptual and theoretical models. Accordingly, the study of his work provides considerable insight into the shifts in theory and technique that affected various attempts to come to grips with the problems of differentiation, development, and morphogenesis while maintaining consistency—and serious contact—with genetics. 2. Because he worked in both European and American settings and maintained extremely rich contacts with workers in numerous disciplines on both sides of the Atlantic, his career sheds light on the various integrative efforts—and tensions—that characterize the relationship between embryology and genetics during the middle of the century. He was intellectually central to a number of key debates, a proponent of an integrative view of the organism that, at times, left him at odds with his colleagues in genetics, a prime mover in the institutionalization of genetics in France, and closely involved with institutional developments elsewhere that reconfigured the map of biology. 3. Ephrussi and his co-workers pioneered a variety of experimental approaches to the analysis of the roles of nuclear and cytoplasmic factors in differentiation. They helped shape the transition from Mendelian transmission genetics to molecular genetics and influenced the transition from embryology to developmental biology.

Recommendations from the EGAPP Working Group: does PCA3 testing for the diagnosis and management of prostate cancer improve patient health outcomes?

Summary of recommendations:The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient evidence to recommend prostate cancer antigen 3 (PCA3) testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination).The EGAPP Working Group found insufficient evidence to recommend PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan.Based on the available evidence, the overall certainty of clinical validity to predict the diagnosis of prostate cancer using PCA3 is deemed “low.” The EGAPP Working Group discourages clinical use for diagnosis unless further evidence supports improved clinical validity.Based on the available evidence, the overall certainty of net health benefit is deemed “low.” The EGAPP Working Group discourages clinical use unless further evidence supports improved clinical outcomes.Rationale:It has been suggested that PCA3 testing in the general male population might lead to earlier diagnosis and management changes (e.g., earlier detection and earlier initiation or higher rates of medical interventions) that improve outcomes. EGAPP Working Group found no direct evidence to support this possibility, so we sought indirect evidence aimed at documenting the extent to which PCA3 testing alters prostate cancer diagnosis or management, alone and in combination with traditional clinical management factors, and the extent to which this testing improves health outcomes.Analytic validity:Assay-related evidence was deemed adequate for the PROGENSA PCA3 assay approved by the US Food and Drug Administration, available from Gen-Probe. Very few studies were available that investigated preanalytical effects, analytical performance, and diagnostic accuracy of other quantitative assays for PCA3.Clinical validity:Evidence on clinical validity was rated inadequate to derive any conclusions about performance of PCA3 testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer, or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination). Furthermore, there was little evidence to derive any conclusions about performance of PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan.Clinical utility:No studies were available to provide direct evidence on the balance of benefits and harms related to PCA3 testing for diagnosis and management in the general male population. Evidence for other populations (e.g., high risk) was not evaluated in the review.Contextual issues:Early diagnosis of prostate cancer is central to minimizing morbidity and mortality. Prevention of prostate cancer mortality is a public health priority. Improvements in outcomes associated with PCA3 testing could have important impacts.Genet Med 2014:16(4):338–346.

Family history and the natural history of colorectal cancer: Systematic review

Purpose:Family history of colorectal cancer (CRC) is a known risk factor for CRC and encompasses both genetic and shared environmental risks.Methods:We conducted a systematic review to estimate the impact of family history on the natural history of CRC and adherence to screening.Results:We found high heterogeneity in family-history definitions, the most common definition being one or more first-degree relatives. The prevalence of family history may be lower than the commonly cited 10%, and confirms evidence for increasing levels of risk associated with increasing family-history burden. There is evidence for higher prevalence of adenomas and of multiple adenomas in people with family history of CRC but no evidence for differential adenoma location or adenoma progression by family history. Limited data regarding the natural history of CRC by family history suggest a differential age or stage at cancer diagnosis and mixed evidence with respect to tumor location. Adherence to recommended colonoscopy screening was higher in people with a family history of CRC.Conclusion:Stratification based on polygenic and/or multifactorial risk assessment may mature to the point of displacing family history–based approaches, but for the foreseeable future, family history may remain a valuable clinical tool for identifying individuals at increased risk for CRC.Genet Med 17 9, 702–712.

Enhancing Genomic Laboratory Reports: A Qualitative Analysis of Provider Review

This study reports on the responses of physicians who reviewed provider and patient versions of a genomic laboratory report designed to communicate results of whole genome sequencing. Semi‐structured interviews addressed concept communication, elements, and format of example genome reports. Analysis of the coded transcripts resulted in recognition of three constructs around communication of genome sequencing results: (1) Providers agreed that whole genomic sequencing results are complex and they welcomed a report that provided supportive interpretation information to accompany sequencing results; (2) Providers strongly endorsed a report that included active clinical guidance, such as reference to practice guidelines, if available; and (3) Providers valued the genomic report as a resource that would serve as the basis to facilitate communication of genome sequencing results with their patients and families. Providers valued both versions of the report, though they affirmed the need for a provider‐oriented report. Critical elements of the report included clear language to explain the result, as well as consolidated yet comprehensive prognostic information with clear guidance over time for the clinical care of the patient. Most importantly, it appears a report with this design has the potential not only to return results but also serves as a communication tool to help providers and patients discuss and coordinate care over time.

Enhancing genomic laboratory reports from the patients' view: A qualitative analysis

The purpose of this study was to develop a family genomic laboratory report designed to communicate genome sequencing results to parents of children who were participating in a whole genome sequencing clinical research study. Semi‐structured interviews were conducted with parents of children who participated in a whole genome sequencing clinical research study to address the elements, language and format of a sample family‐directed genome laboratory report. The qualitative interviews were followed by two focus groups aimed at evaluating example presentations of information about prognosis and next steps related to the whole genome sequencing result. Three themes emerged from the qualitative data: (i) Parents described a continual search for valid information and resources regarding their childs condition, a need that prior reports did not meet for parents; (ii) Parents believed that the Family Report would help facilitate communication with physicians and family members; and (iii) Parents identified specific items they appreciated in a genomics Family Report: simplicity of language, logical flow, visual appeal, information on what to expect in the future and recommended next steps. Parents affirmed their desire for a family genomic results report designed for their use and reference. They articulated the need for clear, easy to understand language that provided information with temporal detail and specific recommendations regarding relevant findings consistent with that available to clinicians.

Recommendations from the EGAPP Working Group: Does genomic profiling to assess type 2 diabetes risk improve health outcomes?

Summary of recommendations:The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found insufficient evidence to recommend testing for predictive variants in 28 variants (listed in Table 1) to assess risk for type 2 diabetes in the general population, on the basis of studies in populations of northern European descent. The EWG found that the magnitude of net health benefit from the use of any of these tests alone or in combination is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes.The EWG found insufficient evidence to recommend testing for the TCF7L2 gene to assess risk for type 2 diabetes in high-risk individuals. The EWG found that the magnitude of net health benefit from the use of this test is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes.On the basis of the available evidence for both the scenarios, the overall certainty of net health benefit is deemed “low.”Rationale:It has been suggested that genomic profiling in the general population or in high-risk populations for type 2 diabetes might lead to management changes (e.g., earlier initiation or higher rates of medical interventions, or targeted recommendations for behavioral change) that improve type 2 diabetes outcomes or prevent type 2 diabetes. The EWG found no direct evidence to support this possibility; therefore, this review sought indirect evidence aimed at documenting the extent to which genomic profiling alters type 2 diabetes risk estimation, alone and in combination with traditional risk factors, and the extent to which risk classification improves health outcomes.Analytic validity:Assay-related evidence on available genomic profiling tests was deemed inadequate. However, on the basis of existing technologies that have been or may be used, the analytic sensitivity and specificity of tests for individual gene variants might be at least satisfactory.Clinical validity:Twenty-eight candidate markers were evaluated in the general population. Evidence on clinical validity was rated inadequate for 24 of these associations (86%) and adequate for 4 (14%). Inadequate grades were based on limited evidence, poor replication, existence of possible biases, or combinations of these factors. Type 2 diabetes genomic profiling provided areas under the receiver operator characteristics curve of 55%–57%, with 4, 8, and 28 genes. Only TCF7L2 had convincing evidence of an association with type 2 diabetes with an odds ratio of 1.39 (95% confidence interval: 1.33–1.46).TCF7L2 was evaluated for high-risk populations, and the overall odds ratio was 1.66 (95% confidence interval: 1.22–2.27) for association with progression to type 2 diabetes.Clinical utility:No studies were available to provide direct evidence on the balance of benefits and harms for genetic profiling for type 2 diabetes alone or in addition to traditional risk factors in the general population.Evidence for high-risk populations and TCF7L2 was inadequate on the basis of two identified studies. These studies found close to zero additional benefit with the addition of genomic markers to traditional risk factors (diet, body mass index, and glucose tolerance).Contextual issues:Prevention of type 2 diabetes is a public health priority. Improvements in the outcomes associated with genomic profiling could have important impacts. Traditional risk factors (e.g., body mass index, weight, fat mass, and exercise) have an advantage in clinical screening and risk assessment strategies because they measure the actual targets for therapy (e.g., fasting plasma glucose and medical interventions). To be useful in predicting disease risk, genomic testing should improve the predictive value of these traditional risk factors. Some issues important for clinical utility remain unknown, such as the level of risk that changes intervention, whether long-term disease outcomes will improve, how individuals being tested will understand/respond to test results and interact with the health-care system, and whether testing will motivate behavior change or amplify potential harms.Genet Med 2013:15(8):612–617