Resolving the evolutionary paradox of genetic instability: a cost–benefit analysis of DNA repair in changing environments

AbstractLoss of genetic stability is a critical phenomenon in cancer and antibiotic resistance, and the prevailing dogma is that unstable cells survive because instability provides adaptive mutations. Challenging this view, we have argued that genetic instability arises because DNA repair may be a counterproductive strategy in mutagenic environments. This paradoxical relationship has also been confirmed by explicit experiments, but the underlying evolutionary principles remain controversial. This paper aims to clarify the issue, and presents a model that explains genetic instability from the basic perspective of molecular evolution and information processing

Unstable DNA Repair Genes Shaped by Their Own Sequence Modifying Phenotypes

The question of whether natural selection favors genetic stability or genetic variability is a fundamental problem in evolutionary biology. Bioinformatic analyses demonstrate that selection favors genetic stability by avoiding unstable nucleotide sequences in protein encoding DNA. Yet, such unstable sequences are maintained in several DNA repair genes, thereby promoting breakdown of repair and destabilizing the genome. Several studies have therefore argued that selection favors genetic variability at the expense of stability. Here we propose a new evolutionary mechanism, with supporting bioinformatic evidence, that resolves this paradox. Combining the concepts of gene-dependent mutation biases and meiotic recombination, we argue that unstable sequences in the DNA mismatch repair (MMR) genes are maintained by their own phenotype. In particular, we predict that human MMR maintains an overrepresentation of mononucleotide repeats (monorepeats) within and around the MMR genes. In support of this hypothesis, we report a 31% excess in monorepeats in 250 kb regions surrounding the seven MMR genes compared to all other RefSeq genes (1.75 vs. 1.34%, P = 0.0047), with a particularly high content in PMS2 (2.41%, P = 0.0047) and MSH6 (2.07%, P = 0.043). Based on a mathematical model of monorepeat frequency, we argue that the proposed mechanism may suffice to explain the observed excess of repeats around MMR genes. Our findings thus indicate that unstable sequences in MMR genes are maintained through evolution by the MMR mechanism. The evolutionary paradox of genetically unstable DNA repair genes may thus be explained by an equilibrium in which the phenotype acts back on its own genotype

Evaluation of the Medical Student Research Programme in Norwegian medical schools. A survey of students and supervisors

Background: The Medical Student Research Programme is a national education and grant scheme for medical students who wish to carry out research in parallel with their studies. The purpose of the programme is to increase recruitment of people with a standard medical degree to medical research. The Research Programme was established in 2002 and underwent a thorough evaluation during the spring of 2007. The evaluation should investigate if the programme had fulfilled its objectives of increased recruitment to medical research, in addition to the students' and supervisors' satisfaction of the programme, and unwanted differences between the universities. Methods: Data was collected from students, supervisors and administrative staff via web-based questionnaires. Information about admission, implementation, results achieved and satisfaction was analysed and compared between the four Norwegian medical schools. In addition, the position of the scheme in relation to the national Quality Reform of Higher Education was analysed. Results: At the end of 2006, the Medical Student Research Programme had recruited 265 medical students to research. These consisted of 214 active students, 35 who had completed their studies and only 17 who had dropped out. Both students and supervisors were generally very satisfied with the scheme, including the curriculum, the results achieved and the administrative service. The majority of students wanted to continue their research towards a PhD and, of those who had completed the Medical Student Research Programme, practically all had published one or several scientific papers. The survey showed only small differences between the four medical schools, despite their choice of somewhat different solutions in terms of administration and organisation. The Medical Student Research Programme satisfies the majority of the demands of the Quality Reform, however as an integrated research programme aimed at a PhD it presupposes access to PhD courses before the completion of medical studies, as well as the ability to include undergraduate scientific work in a PhD thesis. Conclusion: The Medical Student Research Programme has led to an increase in the recruitment of graduated physicians to medical research in Norway. It will only be possible to evaluate whether this in turn will result in a larger number of PhDs in 3–5 years; this will also depend on the access to grants and fellowships.publishedVersio

Leadership and organization change in biomedical PhD education: An instrumental case study of the development of a centralized organization for biomedical graduate studies at the University of Pennsylvania

Biomedical PhD education is a large and increasingly interdisciplinary segment of higher education. The primarily laboratory-based research training is commonly distributed to a range of administrative units within and outside the research-intensive universities. This organizational fragmentation represents a significant challenge to coordination, oversight, and quality development. The University of Pennsylvania was one of the first institutions to establish a centralized, umbrella-type biomedical graduate program to address these organizational challenges. The thirty-year-old program has been highly successful and is regarded as a model for other institutions. In order to learn from the program's path to success, this research investigated the inner dynamics and leadership actions related to the development of Biomedical Graduate Studies (BGS) at the University of Pennsylvania. The retrospective instrumental case study explored the process from the period prior to the establishment of the program in 1984 until its current configuration in 2014. Data were collected through semi-structured interviews with 18 people representing different time periods and leadership positions in the history of the program, as well as archival material. The data were analyzed to establish the chronology of events and to identify the main themes and leadership actions of the change process. The presented case was subsequently analyzed in light of established theory on organizational change and leadership orientations in higher education. This analysis demonstrated that the change was a multi-dimensional process and could be explained by several theoretical frameworks. There were elements of planning and decisive management, organizational learning, political bargaining, adaptation to environmental factors, and attention to culture and symbolism. The process involved a transformation that empowered the junior faculty, promoted collegiality, and improved the quality of recruitment, student satisfaction, and scientific outcomes. Centralization of student recruitment and funding, detaching the graduate education from the department structure, and collaborative leadership stood out as primary factors for success. This case study may serve as a guideline for other institutions that aim to develop centralized biomedical graduate programs. It also represents a reference for further research in the field of biomedical education management

Leadership and organization change in biomedical PhD education: An instrumental case study of the development of a centralized organization for biomedical graduate studies at the University of Pennsylvania

Biomedical PhD education is a large and increasingly interdisciplinary segment of higher education. The primarily laboratory-based research training is commonly distributed to a range of administrative units within and outside the research-intensive universities. This organizational fragmentation represents a significant challenge to coordination, oversight, and quality development. The University of Pennsylvania was one of the first institutions to establish a centralized, umbrella-type biomedical graduate program to address these organizational challenges. The thirty-year-old program has been highly successful and is regarded as a model for other institutions. In order to learn from the program\u27s path to success, this research investigated the inner dynamics and leadership actions related to the development of Biomedical Graduate Studies (BGS) at the University of Pennsylvania. The retrospective instrumental case study explored the process from the period prior to the establishment of the program in 1984 until its current configuration in 2014. Data were collected through semi-structured interviews with 18 people representing different time periods and leadership positions in the history of the program, as well as archival material. The data were analyzed to establish the chronology of events and to identify the main themes and leadership actions of the change process. The presented case was subsequently analyzed in light of established theory on organizational change and leadership orientations in higher education. This analysis demonstrated that the change was a multi-dimensional process and could be explained by several theoretical frameworks. There were elements of planning and decisive management, organizational learning, political bargaining, adaptation to environmental factors, and attention to culture and symbolism. The process involved a transformation that empowered the junior faculty, promoted collegiality, and improved the quality of recruitment, student satisfaction, and scientific outcomes. Centralization of student recruitment and funding, detaching the graduate education from the department structure, and collaborative leadership stood out as primary factors for success. This case study may serve as a guideline for other institutions that aim to develop centralized biomedical graduate programs. It also represents a reference for further research in the field of biomedical education management

The Nine Cancer Frames: A Tool to Facilitate Critical Reading of Cancer-Related Information

Abstract People’s ability to critically assess cancer-related information is essential from a preventional and therapeutic, as well as a general democratic perspective. Such cancer literacy is not just about acquiring factual knowledge. It also involves the ability to analyze how the information is contextualized—how cancer is framed. Previous research concerning the framing of cancer in public discourse is voluminous and penetrating but also fragmented and inaccessible to non-experts. In this study, we have developed an integrated and applicable tool for analyzing cancer discourse by systematically classifying distinctive ways of framing of the concept of cancer. Building on previous research and an inductive framing analysis of a broad range of public cancer discourse, systematically selected from British and Norwegian newspapers, we have characterized nine cancer frames: the biomedical, the environmental, the epidemiological, the personal, the sociopolitical, the economic, the antagonistic, the alternative, and the symbolic frame. This framing scheme may be applied to analyze cancer-related discourse across a plurality of themes and contexts. We also show how different frames combine to produce more complex messages, thereby revealing underlying patterns, strategies, and conflicts in cancer communication. In conclusion, this analytical tool enables critical reading of cancer-related information and may be especially useful in educational initiatives to advance health communication and public understanding of cancer

Evaluation of the medical student research programme in Norwegian medical schools. A survey of students and supervisors

Abstract Background The Medical Student Research Programme is a national education and grant scheme for medical students who wish to carry out research in parallel with their studies. The purpose of the programme is to increase recruitment of people with a standard medical degree to medical research. The Research Programme was established in 2002 and underwent a thorough evaluation during the spring of 2007. The evaluation should investigate if the programme had fulfilled its objectives of increased recruitment to medical research, in addition to the students' and supervisors' satisfaction of the programme, and unwanted differences between the universities. Methods Data was collected from students, supervisors and administrative staff via web-based questionnaires. Information about admission, implementation, results achieved and satisfaction was analysed and compared between the four Norwegian medical schools. In addition, the position of the scheme in relation to the national Quality Reform of Higher Education was analysed. Results At the end of 2006, the Medical Student Research Programme had recruited 265 medical students to research. These consisted of 214 active students, 35 who had completed their studies and only 17 who had dropped out. Both students and supervisors were generally very satisfied with the scheme, including the curriculum, the results achieved and the administrative service. The majority of students wanted to continue their research towards a PhD and, of those who had completed the Medical Student Research Programme, practically all had published one or several scientific papers. The survey showed only small differences between the four medical schools, despite their choice of somewhat different solutions in terms of administration and organisation. The Medical Student Research Programme satisfies the majority of the demands of the Quality Reform, however as an integrated research programme aimed at a PhD it presupposes access to PhD courses before the completion of medical studies, as well as the ability to include undergraduate scientific work in a PhD thesis. Conclusion The Medical Student Research Programme has led to an increase in the recruitment of graduated physicians to medical research in Norway. It will only be possible to evaluate whether this in turn will result in a larger number of PhDs in 3–5 years; this will also depend on the access to grants and fellowships.</p