Studies of congenital genetic aberrations behind childhood leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, and most frequently (85%) of B-cell precursor type (BCP-ALL). Acquired chromosomal rearrangements or aneuploidies are the recurrent, often prenatal, initiators of BCP-ALL. These aberrations define distinct molecular subtypes that are associated with differences in prognosis and used to guide treatment. Initiating variants are disease driving, but secondary variants are required to drive progression to overt disease. Although constitutional predisposing variants are found in an increasing share of cases (10-18%), BCP-ALL etiology remains largely unknown. Recent studies have suggested that exposure to common infections may modulate progression of BCP-ALL. The aim of this thesis was to identify, asses and quantify congenital genetic aberrations behind childhood BCP-ALL predisposition and initiation, as well as to characterize subsequent clonal evolution and identify drivers of progression to overt disease. To this end, we performed whole genome sequencing (WGS) to identify constitutional BCP-ALL-predisposing variants. In paper I, we reported familial predisposition mediated by a constitutional t(12;14), where haploinsufficiency of the powerful transcription factor ETV6 was suggested to cause predisposition. In paper III, monozygotic twins with concordant BCP-ALL shared a constitutional, maternally inherited, novel variant in NF1, predicted to be highly damaging. As none of the carriers has any clinical sign of the cancer syndrome neurofibromatosis type 1 (NF1), we classified the variant to be of unknown significance (VUS), but speculated its possible BCP-ALL-predisposing effect. We developed a sensitive and quantitative method for backtracking BCP-ALL to pre-leukemic clones (paper II), applying chip dPCR in combination with WGS to analyze DNA from neonatal dried blood spots. In paper II, only one case of BCP-ALL, diagnosed at age 1 month, had detectable copy numbers of genomic breakpoint sequence at birth. Failed detection in the remaining six cases was suggested to be caused by technical and sample related limitations, and less frequently postnatal initiation. In paper III, WGS identified a shared somatic complex rearrangement, generating ETV6- RUNX1, in the BCP-ALLs of monozygotic twins. Detection at birth by dPCR failed, but identical breakpoint sequences confirmed its prenatal origin. Surprisingly, a shared (prenatal) deletion in UBA2 was found to precede the complex rearrangement, persisting after several years in remission. Clonal evolution of concordant BCP-ALLs was characterized in paper III, detecting shared and unique overlapping secondary putative driver variants, supporting independent although convergent clonal evolution. In paper I, 7-10 secondary putative driver variants, in genes recurrently targeted in childhood ALL, were identified in BCP-ALLs with ETV6-mediated predisposition. This further supported that secondary drivers are required for progression, although phylogenetics of somatic events in ETV6-predisposed cases remains to be delineated. In paper IV, we assessed a Swedish population-based cohort of 1380 BCP-ALL cases and used GARIMAX to demonstrate informative seasonal variation in onset and interpreted peak onset to fall in August. Four explanatory models, related to exposure to common infections as a driver of final progression to overt disease, were suggested. The likelihood of each model depends on still unknown induction time of childhood BCP- ALL. Together, these studies add to our understanding of; congenital susceptibility to BCP-ALL through constitutional predisposing variants and prenatally initiated pre-leukemic clones, progression to overt disease through somatic clonal evolution and the genetic and environmental drivers of this process

Everyday Automation

This Open Access book brings the experiences of automation as part of quotidian life into focus. It asks how, where and when automated technologies and systems are emerging in everyday life across different global regions? What are their likely impacts in the present and future? How do engineers, policy makers, industry stakeholders and designers envisage artificial intelligence (AI) and automated decision-making (ADM) as solutions to individual and societal problems? How do these future visions compare with the everyday realities, power relations and social inequalities in which AI and ADM are experienced? What do people know about automation and what are their experiences of engaging with ‘actually existing’ AI and ADM technologies? An international team of leading scholars bring together research developed across anthropology, sociology, media and communication studies and ethnology, which shows how by rehumanising automation, we can gain deeper understandings of its societal impacts

Everyday Automation

This Open Access book brings the experiences of automation as part of quotidian life into focus. It asks how, where and when automated technologies and systems are emerging in everyday life across different global regions? What are their likely impacts in the present and future? How do engineers, policy makers, industry stakeholders and designers envisage artificial intelligence (AI) and automated decision-making (ADM) as solutions to individual and societal problems? How do these future visions compare with the everyday realities, power relations and social inequalities in which AI and ADM are experienced? What do people know about automation and what are their experiences of engaging with ‘actually existing’ AI and ADM technologies? An international team of leading scholars bring together research developed across anthropology, sociology, media and communication studies and ethnology, which shows how by rehumanising automation, we can gain deeper understandings of its societal impacts

Reorganizing Biomedical Research : Biobanks as Conditions of Possibility for Personalized Medicine

In recent decades biomedical samples and data have been organized into large depositories such as biobanks. These biobanks have also been founded in Finland to allow for increasingly large-scale, international, and data-intensive biomedical research. Simultaneously expectations of personalized medicine have increased – in the future individuals instead of averages will be treated, and genomic data may be utilized in the clinics or in disease prevention. This study – rooted in science and technology studies, and linking to discussions of the role of expectations and imaginaries – examines biobanks as conditions of possibility for personalized medicine to become reality: that is, how biobanks are expected to make personalized medicine possible. The rearranging of biomedical research through biobanks is investigated against the backdrop of personalized medicine as a sociotechnical imaginary: a vision of a desirable future, which is both built on, and continuously requires, science and technology, and therefore societal efforts, for its fulfillment (Jasanoff and Kim, 2015). Consequently, this study asks: What do the expectations related to biobanks as conditions of possibility for personalized medicine tell us about the knowledge production in which biobanks are supposed to participate, and the role biobanks play in it? To answer this question, biobanking is studied through three different lenses. The analytical sections unpack, first, the claims of high quality samples they store; second, the ideas related to research population(s) seen to be stored in biobanks; and third, their link to the expectations of translational medicine. Thus, it is explored how biobanks are expected and said to contribute to contemporary biomedical knowledge production that takes place in highly regulated settings. The main argument of the study is that the very idea of biobanks is being reshaped as operations, conventions, regulatory frameworks, and new expectations are linked to the imaginary of personalized medicine and require that action be taken. The different layers of stakeholders, regulations, developments, and projects that condition and constrain biobanking and hence knowledge production, have, and continue to have, an effect on what biobanks are considered and understood to be, and the kind of knowledge and scientific practices they could foster. The analytical chapters illustrate the multiplicity of tendencies and linkages attendant on biobanks as they begin to reorganize biomedical research.Biopankkeja on perustettu viime vuosikymmenten aikana organisoimaan ihmisperäisten näytteiden ja niihin liitetyn terveystiedon keräystä, säilytystä ja jakelua. Niitä on pidetty kansainvälisen, data-intensiivisen ja suuriin aineistoihin perustuvan biolääketieteellisen tutkimuksen mahdollistajina. Myös Suomessa on perustettu biopankkeja, joilla nähdään olevan tärkeä rooli yksilöllistetyn, henkilökohtaisen lääketieteen kehittämisessä. Odotus on, että tulevaisuudessa potilaiden hoito voidaan räätälöidä juuri heille sopivaksi. Myös genomitietoa voitaisiin hyödyntää niin potilashoidossa kuin sairauksien ennaltaehkäisyssä. Tässä tieteen ja teknologian tutkimukseen sekä odotusten sosiologiaan kiinnittyvässä tutkimuksessa tarkastellaan biopankkeja henkilökohtaisen lääketieteen toteutumisen edellytyksenä. Biolääketieteellisen tutkimuksen uudelleenjärjestelemistä biopankkien kautta tutkitaan suhteessa henkilökohtaiseen lääketieteeseen. Henkilökohtainen lääketiede nähdään sosioteknisenä kuvitelmana eli näkemyksenä tavoittelemisenarvoisesta tulevaisuudesta (Jasanoff ja Kim, 2015). Tämä tulevaisuuskuva perustuu tieteeseen ja teknologiaan, edellyttää niitä ja näin ollen vaatii siis yhteiskunnallisia toimia toteutuakseen. Tutkimuksessa kysytään: Mitä odotukset biopankeista henkilökohtaisen lääketieteen edellytyksinä paljastavat siitä tiedontuotannosta, johon niiden odotetaan osallistuvan sekä biopankkien itsensä roolista tässä tiedontuotannossa? Kysymykseen vastataan tarkastelemalla biopankkeja kolmesta näkökulmasta. Analyysiosioissa asiaa käsitellään ensinnäkin tarkastelemalla väitettä biopankkien korkealaatuisista näytteistä. Toiseksi huomio kiinnitetään käsityksiin tutkimuspopulaatioista, joita biopankeissa säilytetään. Kolmanneksi analysoidaan biopankkien linkkiä odotuksiin translationaalisesta lääketieteestä. Analyysiosioissa huomio kiinnittyy siihen, miten biopankkien odotetaan osallistuvan tiedontuotantoon ja olevan hyödyksi biolääketieteen tarkkaan säädellyissä käytännöissä. Tutkimuksen pääargumentti on, että idea biopankista muuntuu ja muokkautuu sitä mukaa, kun uusia toimintatapoja, säädöksiä ja odotuksia kiinnittyy kuvitelmaan henkilökohtaisesta lääketieteestä, jonka toteutuminen vaatii toimia. Asiaan eri tavoin liittyvät toimijat, säädökset, kehityskulut, uudet projektit ja avaukset, jotka kaikki ovat samanaikaisesti biopankkitoiminnan jatkuvuuden ehtoja että sen rajoittajia, vaikuttavat siihen mitä biopankkien ymmärretään olevan ja minkälaiseen tiedontuotantoon ne osallistuvat sekä minkälaista tietoa ne voivat tuottaa

Values for a Post-Pandemic Future

This open access book shows how value sensitive design (VSD), responsible innovation, and comprehensive engineering can guide the rapid development of technological responses to the COVID-19 crisis. Responding to the ethical challenges of data-driven technologies and other tools requires thinking about values in the context of a pandemic as well as in a post-COVID world. Instilling values must be prioritized from the beginning, not only in the emergency response to the pandemic, but in how to proceed with new societal precedents materializing, new norms of health surveillance, and new public health requirements. The contributors with expertise in VSD bridge the gap between ethical acceptability and social acceptance. By addressing ethical acceptability and societal acceptance together, VSD guides COVID-technologies in a way that strengthens their ability to fight the virus, and outlines pathways for the resolution of moral dilemmas. This volume provides diachronic reflections on the crisis response to address long-term moral consequences in light of the post-pandemic future. Both contact-tracing apps and immunity passports must work in a multi-system environment, and will be required to succeed alongside institutions, incentive structures, regulatory bodies, and current legislation. This text appeals to students, researchers and importantly, professionals in the field

Data Journeys in the Sciences

This groundbreaking, open access volume analyses and compares data practices across several fields through the analysis of specific cases of data journeys. It brings together leading scholars in the philosophy, history and social studies of science to achieve two goals: tracking the travel of data across different spaces, times and domains of research practice; and documenting how such journeys affect the use of data as evidence and the knowledge being produced. The volume captures the opportunities, challenges and concerns involved in making data move from the sites in which they are originally produced to sites where they can be integrated with other data, analysed and re-used for a variety of purposes. The in-depth study of data journeys provides the necessary ground to examine disciplinary, geographical and historical differences and similarities in data management, processing and interpretation, thus identifying the key conditions of possibility for the widespread data sharing associated with Big and Open Data. The chapters are ordered in sections that broadly correspond to different stages of the journeys of data, from their generation to the legitimisation of their use for specific purposes. Additionally, the preface to the volume provides a variety of alternative “roadmaps” aimed to serve the different interests and entry points of readers; and the introduction provides a substantive overview of what data journeys can teach about the methods and epistemology of research