Ahituv developed  cis -regulation therapy (CRT)  for genetic diseases that are caused due to changes in gene dosage  [ 5 ] [ 6 ]  and adipose manipulation transplantation (AMT) that engineers  fat cells  and implants them for therapeutic benefits. [ 7 ]


The Ahituv Lab investigates  gene regulatory elements  and their relationship to  human diversity  and  disease . [ 4 ]  His lab also focuses on identifying gene regulatory elements and linking  nucleotide variation  within them to various  phenotypes , including morphological differences between species,  drug response , and human disease. [ 8 ]  The lab is one of the developers of massively parallel reporter assays (MPRAs) that allow for high-throughput functional characterization of gene regulatory elements. [ 9 ]


In 2014, Ahituv received the  ASCPT Leon I. Goldberg young investigator award  from  The American Society for Clinical Pharmacology and Therapeutics . [ 10 ] [ 1 ]  In 2024, Ahituv received the Scientific Achievement Award from  The American Society of Human Genetics  (ASHG). [ 11 ]


Orly Alter  is an Israeli-American physicist and research associate professor in the field of  bioengineering  and  human genetics . She has published several papers about her research in genomic signal processing and bladder and brain cancers. She is a professor at the  University of Utah . [ 1 ]


Alter began attending school at  Tel Aviv University  in Israel and graduated in October 1989 magna cum laude with her bachelors of science in physics. [ 1 ]  After receiving her undergraduate degree, she began pursuing her Ph.D. in applied physics at the  Stanford University  in California, USA. She completed her Ph.D. with a thesis on “Quantum Measurement of a Single System," under the mentorship of  Yoshihisa Yamamoto  in January of 1999 [ 2 ]  and then moved onto a postdoctoral fellowship working with genetics, remaining at Stanford. Alter moved to the  University of Utah  in 2010. [ 3 ]


Alter has one published book named  Genomic Signal Processing: Discovery of Principles of Nature from Matrix and Tensor Modeling of Large-Scale Molecular Biological Data . [ 4 ]  Alter's work on finding patterns in DNA finds predictors indicative of a woman's risk for ovarian cancer, [ 5 ]  and she uses mathematical models to improve the outcomes for women with ovarian cancer. [ 6 ]


In 2005 Alter was selected by the  International Linear Algebra Society  to give the Linear Algebra and its Applications Lecture. [ 7 ]


Francisco Ernesto (Tito) Baralle  (born 26 October 1943, in  Buenos Aires ) is an Argentinian geneticist best known for his innovations in molecular biology and in particular the discovery of how genes are processed and mechanisms in mRNA splicing. [ 1 ] [ 2 ] [ 3 ]


Francisco Ernesto (a.k.a. Tito) Baralle was born in  Buenos Aires ,  Argentina  on 26 October 1943. After completing his Ph.D. studies at the Department of Organic Chemistry, he transferred to the Instituto de Investigaciones Bioquimicas Fundacion Campomar directed by Prof.  Luis F. Leloir , now the  Leloir Institute . In 1974, he moved to the MRC Laboratory of Molecular Biology,  Cambridge University , UK, where he worked in the Division directed by Dr.  Frederick Sanger . From (1980 to 1990), he was University Lecturer of Pathology at  Oxford University  and Fellow of  Magdalen College . In 1993, he was awarded the Platinum  Konex Award  for Science and Technology (Argentina) as the best scientist of the decade in Genetics and Cytology.


In September 1990, he was appointed Director of the Trieste Component of  International Centre for Genetic Engineering and Biotechnology  (ICGEB) [1]  an autonomous, intergovernmental organisation originally established under  UNIDO . From 2004-2014 he was the Director-General of the institute, overseeing laboratories in 4 continents, spanning 63 countries championing collaboration, scientific education and dissemination of Science and Biotechnology worldwide.


During his 10 year tenure as Director-General, and as well as expanding his medical and scientific research, he was responsible for the establishment of a  Biotechnology Development Group  serving as a training hub for researchers of developing countries, transferring biopharmaceutical know-how locally.


He was a strong supporter of the internationalization of science and took the 2-component ( Italy  and  India )  International Centre for Genetic Engineering and Biotechnology , and expanded it to 4 component institutions, establishing, and opening new centres in  Africa  and  Argentina , giving opportunities and access to young scientists from the developing world.


In 1977, and as a staff scientist at the laboratory of molecular biology,  Cambridge , Tito published the sequence of the messenger RNA coding for  beta-globin , [ 4 ]  the first complete primary structure of a  eukaryotic [ 5 ]   mRNA . In 1979, his research group isolated the gene for epsilon-globin ( HBE1 ), [ 6 ]  a component of human  embryonic hemoglobin . He was one of the first to describe the pre-mRNA  alternative splicing process  in the 1980s. [ 3 ] [ 7 ] [ 2 ] [ 8 ] [ 9 ]


His studies on how genes are processed described the first sequences within  exons  that control splicing,  exonic splicing enhancer  (ESE) [ 3 ] [ 10 ]  and has since made critical contributions to understanding the molecular mechanisms involved in this important cellular process in health and disease. He first identified the protein called  TDP 43 , [ 1 ] [ 11 ]  that is now known to play a central role in certain neurodegenerative disorders ( Frontotemporal lobar degeneration ,  Amyotrophic lateral sclerosis  and  Alzheimer disease ). Tito Baralle is a leader and innovator in molecular biology and in particular the discovery of how genes are processed and mechanisms in mRNA splicing.


Tito has over 200 scientific publications, [ 15 ]  some of his most cited are:


Academician  Rifat Hadžiselimović  is a  Bosnian   geneticist . He was born in  Šiprage ,  Bosnia and Herzegovina  on 7 January 1944. In 2013, with over 45 years of service, he was appointed Emeritus. He acts as scientific adviser in  Institute for Genetic Engineering and Biotechnology ,  University of Sarajevo . [ 1 ] [ 2 ] [ 3 ] [ 4 ]


Rifat Hadžiselimović is the member of  Academy of Sciences and Arts of Bosnia and Herzegovina  since 2018. [ 5 ]


Rifat Hadžiselimović completed secondary education in Banja Luka after which in 1962 he enrolled at the Faculty of Natural Sciences and Mathematics in Sarajevo. He graduated as a Biology teacher in 1966 and completed his master's degree in Biology (Anthropology) in 1971 at the Faculty of Science and Mathematics, University of Zagreb, Croatia. His Master thesis was entitled "Historical aspect of the change of relative frequency of two allelogens in human populations". He completed his PhD in biology in 1976 at the Faculty of Science,  University of Sarajevo  on the subject of "The Genetics of ABH antigens secretion in the population of Bosnia and Herzegovina".


Since 1966 he has been employed by the Faculty of Science, University of Sarajevo, first as an Assistant Lecturer (1966-1977), then as an Assistant Professor (1977), Associate Professor (1980) and the Professor (1984) on subjects:  Human Genetics ,  Genetic Engineering  and  Biotechnology ,  Molecular Biology ,  Evolution ,  Bioanthropology , and  Biomedicine .


He was as an active member of the Anthropological Society of Yugoslavia and was a co-founder and member of the Association of Genetics in Bosnia and Herzegovina.
From 1984 – 1986 he also served as the Head of the Department of Biology. From 1994 - 2003 he was engaged in the development of the "Postgraduate study of biological sciences" where he was the head of the programme, and from 2007 was the head of the as the "Genetics" field of the programme.


In the period from 1987 to 2001, he was the Director of the  Institute of Genetic Engineering and Biotechnology  (INGEB), and from 2001 he was the Project Coordinator of the DNA Project which was developed in cooperation with the  International Commission on Missing Persons  (ICMP).  He was also engaged as the Scientific Advisor of the institute (INGEB), and from 2006 to 2012 was appointed a chair of the Board of Directors of the institute.


Leon Mutesa  is a  Rwandan  Professor of  human genetics  who serves as the Director of the Center for Human Genetics at the College of Medicine and Health Sciences,  University of Rwanda , a center he established in 2006.  [ 1 ] [ 2 ]  Mutesa obtained his MD from the  University of Rwanda  in 2003 and earned his PhD in 2009 from the  University of Liege , Belgium, where he also completed his postdoc in 2011. Mutesa's career has been marked by involvement in clinical services, academia, research, capacity-building, and health sector management. [ 3 ]


Mutesa is a Rwandan pioneering figure in the field of genetics; he led the development and implementation of Rwanda’s reference center for medical genetics, the only facility of its kind in East Africa. [ 4 ] [ 5 ]  Mutesa is a board member of the  International Vaccine Institute  and serves as president of the Rwanda Down Syndrome Organization, which supports people with  Down syndrome  in Rwanda. [ 6 ] [ 7 ]  In April 2024, he was awarded the African Prize for Lifetime Contribution in Human Genetics by the HUGO- Human Genome Organisation . [ 8 ]


Mutesa attended the  University of Rwanda , where he graduated with a bachelor's degree in  human biology  in 1998. Subsequently, Mutesa continued his enrolment at the institution to pursue a medical and surgical degree; he graduated with a  Bachelor of Medicine, Bachelor of Surgery  in 2003. Since 2009, Mutesa holds a PhD degree in  human genetics  from the  University of Liège , Belgium. [ 9 ]


After graduating with a  Bachelor of Medicine, Bachelor of Surgery  in 2004, Mutesa started working at the  University of Rwanda , College of Medicine and Health Sciences,  as an assistant lecturer. In 2006, he founded the Center for Human Genetics at the institution and became its director. In 2010, he became senior lecturer. In 2015, Mutesa rose to associate professor of human genetics.  [ 10 ]  He has been a visiting professor of  human genetics  at various institutions, including the  University of Liège  in Belgium,  Cheikh Anta Diop University  in Senegal, and he was promoted to the Professor title in 2019. [ 11 ]  His academic dedication has led him to create various postgraduate programs at the University of Rwanda including MSc and PhD in biotechnology and others for strengthening the biopharmaceutical and vaccine manufacturing capacity in Rwanda. He has supervised/mentored over 90 MSc, MMed, PhD, and Post-Doc fellows from Rwanda and overseas universities. [ 12 ]


Between 2009 and 2011, Mutesa was a Director of the Department of Clinical Biology at the  University Teaching Hospital of Kigali  (CHUK), the largest referral hospital in  Rwanda . Subsequently, he was appointed by the  government of Rwanda  as the head of the Medical Research Division at the Rwanda Biomedical Centre, a Rwanda's national health implementation agency established by the  Ministry of Health . His work included coordinating health-related research activities in all national medical institutions; he served until 2013. [ 13 ]  Between 2013 and 2021, Mutesa worked with the  Rwanda National Police  as a consultant for the implementation of the Rwanda Forensic Institute, a laboratory that supports the justice system with evidence based on science and technology for use in courts of law and other justice bodies in  Rwanda . [ 14 ] [ 9 ]  He also contributed to creation of forensic science bachelor’s degree program at the University of Rwanda. Mutesa has been serving as  Editor-in-Chief  for the Rwanda Medical Journal and the Rwanda Public Health Bulletin since 2010 and 2019, respectively. [ 15 ] [ 16 ]


Mutesa has pioneered new development and implementation of a reference center for human genetics and genomics in  Rwanda , which is the only one in the East African Region. [ 17 ]  In 2009, Mutesa joined the  African Society of Human Genetics  (AfSHG) and created the Rwandan Society of Human Genetics (RSHG) in 2016, for which he serves as its president. In 2018, Mutesa led the team that organized and hosted the joint 11th Conference of  AfSHG , 1st Conference of RSHG, and 12th  H3Africa  Consortium Meeting in  Kigali , Rwanda. [ 18 ]


In 2014, Mutesa advocated for health insurance coverage for genetic examinations for patients in Rwanda, and currently, most health insurances cover the  karyotype exam , cytogenetic, and molecular tests. In 2016, Mutesa and Edwige Musabe created the Rwanda Down Syndrome Organization, which trains family members and teachers in Rwanda to support the development of children with  Down syndrome ; in 2021, it was following over 1,000 patients. Mutesa has served as president of the organization since its founding. [ 3 ] [ 19 ]


Mutesa served as Principal Investigator of several research grants from  National Institute of Health  (NIH) among others, which aimed at characterizing the intergenerational transmission of epigenetic impact of genocide exposure and post-traumatic stress disorder (PTSD) in women survivors of the  1994 genocide against the Tutsi  in Rwanda and their offspring. [ 20 ]  This was one of the most significant scientific endeavors, and the proof of concept showing that in utero genocide exposure was connected to  CpGs  in 3 of the 24 DMRs:  BCL-6 corepressor  (BCOR), PR/SET Domain 8 (PRDM8), and Von Willebrand Factor D and EGF Domains (VWDE), with higher DNAm in exposed vs. unexposed offspring. [ 21 ]  Furthermore, BCOR and VWDE demonstrate a significant correlation between brain and blood DNAm within individuals, suggesting that these peripherally derived signals of genocide exposure may have implications for the brain. These findings indicate that  PTSD  continues to be a burden not only for those who were directly exposed to the  1994 genocide against the Tutsi , but also for future generations. Several potential biological markers were identified, including cortisol levels and a number of epigenetic alterations, and some of which were shared between generations (mother and affected offspring). This study's findings have a comparative effect on populations living in regions with persistent trauma conflicts resulting from war and other forms of violence. Mutesa’s studies have shed light on the mechanisms by which epigenetic modifications impact cellular processes and contribute to various health conditions, advancing the knowledge of how epigenetic regulation affects gene function and providing insights for developing novel therapeutic strategies. [ 22 ]


Mutesa also has investigated how epigenetic modifications affect gene expression and contribute to disease. His research, including a 2020 study on the immune response to  COVID-19 , has focused on understanding how environmental factors and genetic predispositions interact to influence epigenetic changes. These modifications can have profound implications for health and disease. [ 23 ]  Mutesa’s studies have shed light on the mechanisms by which epigenetic modifications impact cellular processes and contribute to various health conditions, advancing the knowledge of how epigenetic regulation affects gene function and providing insights for developing novel therapeutic strategies. [ 24 ]


Mutesa has made notable contributions to the field of  human genetics , focusing on genetic variations and their implications for health. His research has explored the genetic underpinnings of various diseases, including rare genetic disorders prevalent in specific populations. For instance, his 2016 study on  Down syndrome  emphasized the increased burden associated with advanced maternal age in the African context. [ 25 ]  By analyzing genetic data, Mutesa has helped identify genetic markers associated with disease susceptibility and progression, leading to a better understanding of the genetic factors influencing health outcomes. His work has provided valuable insights into the genetic and genomic basis of disease, which are crucial for developing targeted therapeutic interventions and improving diagnostic methods. [ 18 ]


Between July 2004 and July 2006, Mutesa led a study about neonatal screening for  sickle cell disease  in Central Africa, where 1825 newborns with a new  ELISA test  from Burundi, Rwanda, and the East of the Democratic Republic of the Congo were examined. [ 26 ]  Since 2007, Mutesa has conducted various studies on  Down syndrome , particularly in Africa. [ 27 ]


Mutesa’s research on  malaria  has significantly contributed to understanding the disease's genetic and environmental factors, influencing susceptibility and treatment responses. [ 28 ]  His studies have explored malaria epidemiology, identifying genetic markers that could affect disease progression and treatment outcomes. [ 29 ]  Mutesa's work has helped enhance public health strategies aimed at malaria prevention and management, supporting efforts to reduce transmission and improve patient care through targeted interventions. [ 30 ] [ 31 ]  His contributions continue to impact malaria research, particularly in the context of African populations, where malaria remains a major public health challenge. [ 32 ]


As a geneticist, during  COVID-19 , Mutesa was among the Rwandan government’s COVID-19 task force, where he was coordinating  COVID-19  laboratory testing under  WHO  consultancy. [ 33 ]  Mutesa and his research group implemented various research projects aiming at building human capacity for  SARS-CoV-2  laboratory diagnostic and management in Rwanda. [ 34 ]  They discovered a  COVID-19  pooling testing strategy that shows a cost-saving approach for better use of  SARS-CoV-2  limited testing resources, and they published a  Nature’s  paper on their discovery. [ 35 ]  His  work on genomic surveillance of  SARS-CoV-2  had a positive impact for understanding the geographical phylogenetic dynamic of variants during the pandemic. [ 36 ]


Mutesa’s research on  COVID-19  has been comprehensive and instrumental in understanding the pandemic’s impact and response strategies. His contributions include detailed analyses of Rwanda’s preparedness activities and response updates from 2020, examining the role of media in managing the crisis, and evaluating the effectiveness of technologies used in COVID-19 containment. Mutesa’s 2020 work also addressed the implications of easing lockdown restrictions and reviewed global treatment trends. Additionally, his 2021 study investigated the observed lower-than-predicted mortality rates in Rwanda, [ 37 ]  while his 2022 research highlighted innovative approaches, such as the use of trained scent dogs for detecting COVID-19. [ 38 ]  His research played a critical role in shaping public health strategies and responses to the pandemic. [ 39 ]


Mutesa involved in the improvement of clinical trial ecosystem in Rwanda and has contributed to the development of national investment case of clinical trial guidelines. In 2022, he led 2 major clinical trials, one on  malaria , a multi-center Phase III randomized controlled non-inferiority clinical trial, a study by the Development of Triple Artemisinin Combination Therapies (DeTACT),  and another on the COVID-19  mRNA vaccine  candidate, a Phase I/IIa trial funded by  Oxford  and the  International Vaccine Institute , respectively. [ 40 ] [ 1 ]


John Marioni  is a Senior Vice President and Head of Computation at  Genentech  Research and Early Development (gRED) in South San Francisco. [ 2 ]  Previously he was the Head of Research at the  European Bioinformatics Institute  and held an appointment at the  Wellcome Sanger Institute  and the  Cancer Research UK Cambridge Institute  in  Cambridge University . [ 3 ]  He is a computational biologist known for his research on statistical and computational methods for the analysis of genomics data, in particular  single-cell biology  and evolutionary genomics. He continues to co-chair the  Human Cell Atlas  Analysis Working Group. [ 4 ]


Marioni has conducted influential studies in whole-tissue and single-cell  transcriptomics . [ 5 ]  He received his  PhD  from the  University of Cambridge  in Applied Mathematics in 2008. He conducted postdoctoral studies in the  University of Chicago  under  Matthew Stephens . [ 6 ] [ 7 ]


Marioni is known for "pioneering the statistical analysis of gene expression patterns in individual cells, which has led to a radical paradigm shift in the field of transcriptomics." [ 8 ]


Esperanza Martínez-Romero  is a researcher and head of the Genomic Ecology Program at the Center for Genomic Sciences (CCG) of the  National Autonomous University of Mexico  (UNAM) in  Cuernavaca , Mexico. She was awarded  the  L'Oréal-UNESCO For Women in Science Award  in 2020. [ 2 ] [ 3 ] [ 4 ]


Martínez-Romero studies the mutualistic symbioses of bacteria with Mexico's plants and animals using  metagenomics  and  functional genomics  approaches. She was a pioneer in the molecular study of the  nitrogen fixing  symbiosis of beans and the  endophytes  of corn and beans. [ 4 ]  She described new plant and insect bacteria from Mexico. Some of them are species of nitrogen-fixing bacteria. The strains she obtained are deposited in official bacterial collections. Some of them are used as inoculants or biofertilizers in agriculture. She is a postgraduate professor at the  Universidad Nacional Autónoma de México , where she also studied. [ 4 ]  She has received several awards, including the  L'Oréal-UNESCO Awards for Women in Science  in 2020. [ 5 ]  She has published 243 scientific works that together gather more than 9500 external citations ( SCOPUS ).


Since her childhood, Martínez-Romero had access to her father's biology books. [ 3 ]  Her mother worked as a principal in an elementary school. Esperanza completed her bachelor's, master's and doctorate studies in biomedical research at UNAM. [ 6 ]


Martínez-Romero studied Biomedical Research at the  National Autonomous University of Mexico  (UNAM) to obtain her bachelor's, master's, and Ph.D. degree. She did postdoctoral research at the  National Institute for Agricultural Research  of  Toulouse , France. She has also completed research stays in Sweden, Germany, Brazil, and sabbaticals at the  University of California, Davis . [ 6 ]


She began her career researching nitrogen fixation, [ 1 ]  with the idea of applying this knowledge to agriculture. [ 7 ]  She is an expert in ecology and microbial diversity, she has described several species of  Rhizobium , one of the bacterial genera known as nitrogen fixers and  symbionts  of plants. In 1991 Esperanza discovered the species  Rizobium tropici  a symbiont species of the bean  [ 8 ]  now used extensively as an inoculant.


In 2005 she was president of an international committee on taxonomy and president of the Mexican Association of Microbiology, [ 1 ]  due to her interest in microbial ecology since 2016. [ 9 ]


Martínez-Romero carried out the first molecular characterizations of the rhizobia species that form nitrogen-fixing nodules in beans, which is the legume with the highest human consumption in the world. She believe that nitrogen fixation is key to the development of sustainable agriculture, and has explored bacteria from nitrogen-fixing corn trees and in 2022 from animals such as the Tamaulipas tortoise, endangered rabbits, and various insects native to Mexico. [ 10 ]  She is an enthusiast of  microbiome  studies, a new area of knowledge, and she seeks to promote it in Mexico by giving classes, conferences, and she has organized national and international congresses on the microbiome. All plants and animals live with microbes and this coexistence (symbiosis) is the general strategy of life, and  Martínez investigates the mutualistic symbioses of bacteria with plants and animals native to Mexico with metagenomic and functional genomics approaches. She has described new species of plant and insect bacteria from Mexico, some of them nitrogen fixers, which open the possibility to explore nitrogen fixation in animals. [ citation needed ]  Some of the bacteria she described are used as inoculants or biofertilizers in agriculture. A species of  Rhizobium  was proposed by colleagues in the field under its name,  Rhizobium esperanzae . She has given a good number of interviews on radio and television programs. [ citation needed ]


She has published over 200 articles in international indexed journals, book chapters, and various popular articles. [ citation needed ]  She has organized national events and international congresses, in 2020 she organized the National Congress of Microbiome and in 2021 the Latin American Congress of Microbiome online. [ citation needed ]


Martínez-Romero received the research award in Natural Sciences from the Mexican Academy of Sciences (1997), the UNAM Juana Ramírez de Asbaje Recognition (2003), the National University Award for Research in Natural Sciences (2005) and the Agrobio Award (2011). .


In 2020, she received the international award from L'oreal UNESCO for her trajectory in improving crop yields by reducing the use of chemical fertilizers through the use of environmentally friendly bacteria.


Johann Karl Nestler ,  Czech :  Jan Karel Nestler  (16 December 1783 – 9 July 1842) was an Austrian-Czech scientist in the field of hereditary traits, professor of natural history and agriculture at the  Philosophical Faculty of University of Olomouc , dean of the faculty and rector of the university, and doyen of the Czech agriculture science.


Nestler studied philosophy, theology and law in years 1800–06 at the  Olomouc Academical Lyceum  (the University of Olomouc was degraded to academical lyceum in 1782–1826). Then in years 1806–12 he was an educator in  Althart / Staré Hobzí  and in years 1812–18 he was a director of a high school in  Klafterbrunn ,  Lower Austria . In years 1818–20 he received technical education in agriculture. He studied agriculture at the  University of Vienna  in years 1820–21, where he later also worked as  adjunct  at the Department of Agriculture. [ 1 ] [ 2 ]


In year 1823 Nestler became the professor of agriculture, and in 1824 also of natural history, at the  Academy of Nobility  and at the  academical lyceum  in  Olomouc . After the lyceum was restored to University status, Nestler obtained  Doctorate of Philosophy . In 1835 he became the rector of the University and in 1837 he became the dean of its  Faculty of Philosophy . [ 1 ] [ 2 ]


The history of science forces us to think more than science alone can reveal.


During his teaching Nestler included a special section dealing with scientific animal and plant breeding. His main emphasis was on sheep breeding to improve wool protection for the benefit of the textile industry. In his published lectures Nestler (1829) encouraged sheep breeders to elaborate the theoretical basis of the selection process. Nestler also tried to explain how nature produces new species of animals and plants through forces beyond the hand of man and how breeders control the reproductive process and use modifications, such as inbreeding or outcrossing, for increased production. [ 4 ]


Through the examination of the registers of the best stock animals and their offspring Nestler hoped to explain the  German :  Vererbungsgeschichte  (genetic history). Examination of the records of the ancestors of the best breeding animals, called by Nestler  developmental history  ( German :  Entwicklunggeschichte ) was for him the reverse side of the same coin. [ 4 ]  According to Wood and Orel the search for rules of heredity in sheep created an atmosphere of enquiry about heredity in general, which had influence on later work of  Gregor Johann Mendel , himself a student at the Faculty of Philosophy in 1840–43. [ 3 ]


Nestler was also a very active member of the  Moravian-Silesian Society for Advancement of Agriculture  ( German :  Mähr.-Schles. Ges. zur Beförderung des Ackerbaues, Natur- und Landeskde. , in which he, among other things, organized the  4th International Congress of Farmers and Foresters  (1st time in the lands under control of  Austrian Habsburgs ) in  Brno  in 1840. He was also member of many similarly oriented associations and wrote a lot of literature on the topic. [ 1 ] [ 2 ]


Ana Lúcia Silva de Passos  (born 30 May 1967) is a politician and biologist. From 2015 to 2021, she was a member of the  Assembly of the Republic  of  Portugal .


Ana Passos was born on 30 May 1967. She has a doctorate in genetics and molecular biology, and works as a biologist. [ 1 ]


Passos belongs to the  Socialist Party , and from 4 October 2015 to 4 December 2021, she was a member of the  Assembly of the Republic  of  Portugal , from the constituency of the  Faro District . [ 1 ] [ 2 ]


Kermit Ritland  is an ecologist and  geneticist . He is a professor for the Department of Forest and Conservation Sciences at the  University of British Columbia . [ 1 ]


Ritland is most known for his research in  ecology ,  genetics , and  genomics , with a specific focus on forest populations and  plant mating systems . [ 2 ]  He was part of the world's first tree  genome project  which was a collaborative effort involving 34 institutions. He secured a  Canada Foundation for Innovation  (CFI) Grant to fund his research in forest genomics. He also conducted studies on the genetics of  spirit bears , a white morph of the  American black bear , collecting hair samples to contribute to the understanding of the factors influencing their unique coloration. [ 3 ]


Ritland obtained his Bachelor of Science from the  University of Washington, Seattle , and completed his Ph.D. in 1982 at the  University of California, Davis , with a specialization in  botany  and  genetics . [ 4 ]


Ritland has researched  plant biology  and  genetics , [ 5 ]  to examine the sequenced genomes of major land plant lineages. His work has spanned population and  quantitative genetics , with a particular emphasis on plant mating systems, contributing to the development of novel statistical methods in genetics and genomics, especially in the context of  conservation genetics  in forest trees. [ 4 ]


Ritland has explored the impact of climate change on forest trees, particularly the consequences of gene flow. He proposed a mixed mating model for multiple unlinked loci with Subodh Jain, outlining a procedure to estimate outcrossing rates using genotypic data from families. [ 6 ]  In 1996, he introduced Method-of-Moments Estimators for two-gene coefficients of relationship and inbreeding, along with four-gene Cotterman coefficients. [ 7 ]  He alongside Michael Lynch, introduced regression estimators for joint estimation of two-gene and four-gene coefficients of relationship using codominant molecular markers in randomly mating populations. [ 8 ]  His study on plant mating systems published in  Heredity  presented four model extensions using genetic markers, providing formulas for method-of-moments estimators for individual outcrossing rates in both gymnosperms and angiosperms. [ 9 ]  In addition, he investigated the balance of positive and negative consequences of gene flow in different distribution sections, suggesting integrated research in dispersal biology. [ 10 ]


Ritland has made contributions to forest genetics for sustainable management and conservation. He reported the draft genome of the black cottonwood tree using shotgun sequence assembly and genetic mapping, resulting in a chromosome-scale reconstruction that unveiled over 45,000 putative protein-coding genes. [ 11 ]  He also contributed to a 2013  Nature  publication presenting the draft assembly of the 20-gigabase genome of Norway spruce, identifying novel genomic features. [ 12 ]  In a study on scalable bioinformatics tools, he and fellow researchers provided genomics resources for forest management and conservation by utilizing Illumina platforms and ABySS software for whole-genome shotgun sequencing. This approach yielded a 20.8 giga base pairs draft genome of white spruce (Picea glauca) assembled into 4.9 million scaffolds. [ 13 ]


Ritland introduced a mating system model for partially selfing populations by employing electrophoretic markers in two  Mimulus guttatus  populations and proposed marker loci with multiple alleles as a potential solution. [ 14 ]  In addressing the challenge of developing simple sequence repeat (SSR) markers in conifer genomes, he, along with collaborators, utilized expressed sequence tags (ESTs) from a 20,275-unigene spruce dataset, identifying 44 EST-SSR markers. [ 15 ]  He investigated vascular and interfascicular fiber differentiation along the bolting stems axis in Arabidopsis by utilizing global transcript profiling with an  Arabidopsis  full-genome longmer microarray, revealing 182 upregulated transcription factors linked to fiber development. [ 16 ]


Adeno-associated viruses  ( AAV ) are small viruses that infect humans and some other  primate species . They belong to the  genus   Dependoparvovirus , which in turn belongs to the  family   Parvoviridae . They are small (approximately 26  nm  in diameter)  replication-defective ,  nonenveloped viruses  and have linear single-stranded  DNA  (ssDNA) genome of approximately 4.8  kilobases  (kb). [ 1 ] [ 2 ]


Several features make AAV an attractive candidate for creating  viral vectors  for  gene therapy , and for the creation of  isogenic human disease models . [ 3 ]  Gene therapy  vectors  using AAV can infect both dividing and quiescent cells and persist in an extrachromosomal state without integrating into the  genome  of the host cell. In the native virus, however, integration of virally carried genes into the host genome does occur. [ 4 ]  Integration can be important for certain applications, but can also have unwanted consequences. Recent human clinical trials using  AAV for gene therapy in the retina  have shown promise. [ 5 ]


In March 2023, a series of  Nature  papers detected high titres of adeno-associated virus 2 (AAV2), alongside adenovirus and herpesvirus, in samples from a wave of childhood hepatitis. [ 6 ]  One paper suggested that AAV2 co-infection may contribute to more serious liver disease than infection with only adeno- or herpesviruses and that the causal link remains to be established. [ 7 ]


The adeno-associated virus (AAV), previously thought to be a contaminant in adenovirus preparations, was first identified as a  dependoparvovirus  in the 1960s in the laboratories of Bob Atchison at Pittsburgh and  Wallace Rowe  at  NIH . Serological studies in humans subsequently indicated that, despite being present in people infected by  helper viruses  such as adenovirus or herpes virus, AAV itself did not cause any disease. [ 8 ]


Wild-type AAV has attracted considerable interest from gene therapy researchers due to a number of features. Chief amongst these was the virus's apparent lack of pathogenicity. It can also infect non-dividing cells and has the ability to stably integrate into the host cell genome at a specific site (designated AAVS1) in the human  chromosome 19 . [ 9 ] [ 10 ]  This feature makes it somewhat more predictable than  retroviruses , which present the threat of a random insertion and of mutagenesis, which is sometimes followed by development of a cancer. The AAV genome integrates most frequently into the site mentioned, while random incorporations into the genome take place with a negligible frequency. Development of AAVs as gene therapy vectors, however, has eliminated this integrative capacity by removal of the  rep  and  cap  from the  DNA  of the vector. The desired gene together with a promoter to drive transcription of the gene is inserted between the  inverted terminal repeats  (ITRs) that aid in  concatemer  formation in the nucleus after the single-stranded vector DNA is converted by host cell DNA polymerase complexes into double-stranded DNA. AAV-based gene therapy vectors form  episomal  concatemers in the host cell nucleus. In non-dividing cells, these concatemers remain intact for the life of the host cell. In dividing cells, AAV DNA is lost through cell division, since the episomal DNA is not replicated along with the host cell DNA. [ 11 ]  Random integration of AAV DNA into the host genome is detectable but occurs at very low frequency. [ 11 ]  AAVs also present very low  immunogenicity , seemingly restricted to generation of neutralizing  antibodies , while they induce no clearly defined  cytotoxic response . [ 12 ] [ 13 ] [ 14 ]  This feature, along with the ability to infect  quiescent cells  present their dominance over  adenoviruses  as vectors for human  gene therapy . [ citation needed ]


Use of the virus does present some disadvantages. The cloning capacity of the vector is relatively limited and most therapeutic genes require the complete replacement of the virus's 4.8 kilobase genome. Large genes are, therefore, not suitable for use in a standard AAV vector. Options are currently being explored to overcome the limited coding capacity:


Because of AAV's specialized gene therapy advantages, researchers have created an altered version of AAV termed  self-complementary adeno-associated virus (scAAV) . Whereas AAV packages a single strand of DNA and must wait for its second strand to be synthesized, scAAV packages two shorter strands that are complementary to each other. By avoiding second-strand synthesis, scAAV can express more quickly, although as a caveat, scAAV can only encode half of the already limited capacity of AAV. [ 17 ]  Recent reports suggest that scAAV vectors are more immunogenic than single stranded adenovirus vectors, inducing a stronger activation of  cytotoxic T lymphocytes . [ 18 ]


Humoral immunity instigated by infection with the wild type is thought to be common. The associated neutralising activity limits the usefulness of the most commonly used serotype AAV2 in certain applications. Accordingly, the majority of clinical trials under way involve delivery of AAV2 into the brain, a relatively immunologically privileged organ. In the brain, AAV2 is strongly neuron-specific. [ citation needed ]


As of 2019, AAV vectors have been used in over 250 clinical trials worldwide, approximately 8.3% of virus-vectored gene-therapy trials. [ 19 ]  Recently, promising results have been obtained from Phase 1 and Phase 2 trials for a number of diseases, including  Leber's congenital amaurosis , [ 5 ] [ 20 ] [ 21 ]   hemophilia , [ 22 ]   congestive heart failure , [ 23 ]   spinal muscular atrophy , [ 24 ]   lipoprotein lipase deficiency , [ 25 ]  and  Parkinson's disease . [ 26 ]


AAV based gene therapy products have entered the worldwide market following completion of successful clinical trials. The table below contains  FDA  approved gene therapies that have entered the American Market and possibly other markets.


The AAV genome is built of single-stranded deoxyribonucleic acid (ss DNA ), either positive- or negative-sensed, which is about 4.7 kilobase long. The genome comprises ITRs at both ends of the DNA strand, and two  open reading frames  (ORFs):  rep  and  cap . The former is composed of four  overlapping genes  encoding Rep proteins required for the AAV life cycle, and the latter contains overlapping nucleotide sequences of  capsid  proteins: VP1, VP2 and VP3, which interact to form a capsid with icosahedral symmetry. [ 36 ]


The inverted terminal repeat (ITR) sequences comprise 145 bases each. They were named so because of their symmetry, which was shown to be required for efficient multiplication of the AAV genome. [ 37 ]  The feature of these sequences that gives them this property is their ability to form a  hairpin , which contributes to so-called self-priming that allows  primase -independent synthesis of the second DNA strand. The ITRs were also shown to be required for both integration of the AAV DNA into the host cell genome (19th chromosome in humans) and rescue from it, [ 38 ] [ 39 ]  as well as for efficient  encapsidation  of the AAV DNA combined with generation of a fully assembled,  deoxyribonuclease -resistant AAV particles. [ 40 ]


With regard to gene therapy, ITRs seem to be the only sequences required  in cis  next to the therapeutic gene: structural ( cap ) and packaging ( rep ) proteins can be delivered  in trans .  With this assumption many methods were established for efficient production of recombinant AAV (rAAV) vectors containing a  reporter  or therapeutic gene.  However, it was also published that the ITRs are not the only elements required  in cis  for the effective replication and encapsidation.  A few research groups have identified a sequence designated  cis-acting Rep-dependent element  (CARE) inside the coding sequence of the  rep  gene.  CARE was shown to augment the replication and encapsidation when present  in cis . [ 41 ] [ 42 ] [ 43 ] [ 44 ]


On the "left side" of the genome there are two  promoters  called p5 and p19, from which two overlapping messenger ribonucleic acids ( mRNAs ) of different length can be produced. Each of these contains an  intron  which can be either  spliced  out or not. Given these possibilities, four various mRNAs, and consequently four various Rep proteins with overlapping sequence can be synthesized. Their names depict their sizes in  kilodaltons  (kDa): Rep78, Rep68, Rep52 and Rep40. [ 45 ]  Rep78 and 68 can specifically bind the  hairpin  formed by the ITR in the self-priming act and cleave at a specific region, designated terminal resolution site, within the hairpin. They were also shown to be necessary for the AAVS1-specific integration of the AAV genome. All four Rep proteins were shown to bind  ATP  and to possess  helicase  activity. It was also shown that they upregulate the transcription from the p40 promoter (mentioned below), but downregulate both p5 and p19 promoters. [ 39 ] [ 45 ] [ 46 ] [ 47 ] [ 48 ] [ 49 ]


The right side of a positive-sensed AAV genome encodes overlapping sequences of three capsid proteins, VP1, VP2 and VP3, and two accessory proteins, MAAP & AAP, which start from one promoter, designated p40. The molecular weights of these proteins are 87, 72 and 62 kiloDaltons, respectively. [ 50 ]  The AAV capsid is composed of a mixture of VP1, VP2, and VP3 totaling 60 monomers arranged in  icosahedral  symmetry in a ratio of 1:1:10, [ 51 ]  with an empty mass of approximately 3.8  MDa . [ 52 ]
The  crystal structure  of the VP3 protein was determined by Xie, Bue,  et al. [ 53 ]


The  cap  gene produces an additional, non-structural protein called the Assembly-Activating Protein (AAP). This protein is produced from ORF2 and is essential for the capsid-assembly process. [ 54 ]  The exact function of this protein in the assembly process and its structure have not been solved to date. [ citation needed ]


All three VPs are translated from one mRNA. After this mRNA is synthesized, it can be spliced in two different manners: either a longer or shorter intron can be excised resulting in the formation of two pools of mRNAs: a 2.3 kb- and a 2.6 kb-long mRNA pool. Usually, especially in the presence of adenovirus, the longer intron is preferred, so the 2.3-kb-long mRNA represents the so-called "major splice". In this form the first  AUG codon , from which the synthesis of VP1 protein starts, is cut out, resulting in a reduced overall level of VP1 protein synthesis. The first AUG codon that remains in the major splice is the initiation codon for VP3 protein. However, upstream of that codon in the same open reading frame lies an ACG sequence (encoding threonine) which is surrounded by an optimal  Kozak context . This contributes to a low level of synthesis of VP2 protein, which is actually VP3 protein with additional N terminal residues, as is VP1. [ 55 ] [ 56 ] [ 57 ] [ 58 ]


Since the bigger intron is preferred to be spliced out, and since in the major splice the ACG codon is a much weaker  translation  initiation signal, the ratio at which the AAV structural proteins are synthesized  in vivo  is about 1:1:20, which is the same as in the mature virus particle. [ 59 ]  The unique fragment at the N terminus of VP1 protein was shown to possess the  phospholipase  A2 (PLA2) activity, which is probably required for the releasing of AAV particles from late  endosomes . [ 60 ]  Muralidhar  et al.  reported that VP2 and VP3 are crucial for correct virion assembly. [ 57 ]  More recently, however, Warrington  et al.  showed VP2 to be unnecessary for the complete virus particle formation and an efficient infectivity, and also presented that VP2 can tolerate large insertions in its N terminus, while VP1 can not, probably because of the PLA2 domain presence. [ 61 ]


Recent discoveries made through use of high-throughput 'omics approaches include the fact that AAV capsids are post-translationally modified (PTM) during production such as acetylation, methylation, phosphorylation, deamidation, O-GlycNAcylation [ 62 ]  and SUMOylation throughout capsid proteins VP1, VP2 and VP3. These PTMs differ depending on the manufacturing production platform. Another such discovery is the fact that AAV genomes are epigenetically methylated during production. Besides price, these findings might affect expression kinetics, rAAV receptor binding, trafficking, vector immunogenicity, and expression durability. [ 63 ] [ 64 ]


Two species of AAV were recognised by the  International Committee on Taxonomy of Viruses  in 2013:  adeno-associated dependoparvovirus A  (formerly AAV-1, −2, −3 and −4) and  adeno-associated dependoparvovirus B  (formerly AAV-5). [ 66 ]


Until the 1990s, virtually all AAV biology was studied using AAV serotype 2. However, AAV is highly prevalent in humans and other primates and several serotypes have been isolated from various tissue samples. Serotypes 2, 3, 5, and 6 were discovered in human cells, AAV serotypes 1, 4, and 7–11 in nonhuman primate samples. [ 67 ]  As of 2006 there have been 11 AAV  serotypes  described, the 11th in 2004. [ 68 ]  AAV capsid proteins contain 12 hypervariable surface regions, with most variability occurring in the threefold proximal peaks, but the parvovirus genome in general presents highly conserved replication and structural genes across serotypes. [ 67 ]  All of the known serotypes can infect cells from multiple diverse tissue types. Tissue specificity is determined by the capsid serotype and pseudotyping of AAV vectors to alter their tropism range will likely be important to their use in therapy.


Serotype 2 (AAV2) has been the most extensively examined so far. [ 69 ] [ 70 ] [ 71 ] [ 72 ] [ 73 ] [ 74 ]  AAV2 presents natural tropism towards  skeletal muscles , [ 75 ]   neurons , [ 69 ]   vascular smooth muscle  cells [ 76 ]  and  hepatocytes . [ 77 ]


Three cell receptors have been described for AAV2:  heparan sulfate proteoglycan  (HSPG), a V β 5   integrin  and  fibroblast growth factor  receptor 1 (FGFR-1). The first functions as a primary receptor, while the latter two have a co-receptor activity and enable AAV to enter the cell by receptor-mediated  endocytosis . [ 78 ] [ 79 ] [ 80 ]  These study results have been disputed by Qiu, Handa,  et al. [ 81 ]  HSPG functions as the primary receptor, though its abundance in the  extracellular matrix  can scavenge AAV particles and impair the infection efficiency. [ 82 ]


Studies have shown that serotype 2 of the virus (AAV-2) apparently kills cancer cells without harming healthy ones.  "Our results suggest that adeno-associated virus type 2, which infects the majority of the population but has no known ill effects, kills multiple types of cancer cells yet has no effect on healthy cells," said Craig Meyers, [ 83 ]  a professor of  immunology  and  microbiology  at the  Penn State  College of Medicine in  Pennsylvania  in 2005. [ 84 ]  This could lead to a new anti-cancer agent.


In March 2023, a series of  Nature  papers linked infection of adeno-associated virus 2 (AAV2) to a wave of childhood hepatitis. [ 6 ]


Although AAV2 is the most popular serotype in various AAV-based research, it has been shown that other serotypes can be more effective as gene delivery vectors. AAV9 passes the  blood-brain-barrier  in humans, AAV6 appears much better in infecting airway epithelial cells, [ 85 ] [ 86 ]  AAV7 presents very high transduction rate of murine skeletal muscle cells (similar to AAV1 and AAV5), AAV8 transduce hepatocytes [ 87 ] [ 88 ] [ 89 ]  and AAV1 and 5 were shown to be very efficient in gene delivery to vascular endothelial cells. [ 90 ]  In the brain, most AAV serotypes show neuronal tropism, while AAV5 also transduces astrocytes. [ 91 ]  AAV6, a hybrid of AAV1 and AAV2, [ 89 ]  also shows lower immunogenicity than AAV2. [ 88 ]


Serotypes can differ with the respect to the receptors they are bound to. For example, AAV4 and AAV5 transduction can be inhibited by soluble  sialic acids  (of different form for each of these serotypes), [ 92 ]  and AAV5 was shown to enter cells via the  platelet-derived growth factor  receptor. [ 93 ]


There have been many efforts to engineer and improve new AAV variants for both clinical and research purposes. Such modifications include new tropisms to target specific tissues, and modified surface residues to evade detection by the immune system. Beyond opting for particular strains of  recombinant AAV  (rAAV) to target particular cells, researchers have also explored AAV pseudotyping, the practice of creating hybrids of certain AAV strains to approach an even more refined target. The hybrid is created by taking a capsid from one strain and the genome from another strain. For example:


Other efforts to engineer and improve new AAV variants have involved the  ancestral reconstruction  of virus variants to generate new vectors with enhanced properties for clinical applications and the study of AAV biology. [ 96 ]


AAV is of particular interest to gene therapists due to its apparent limited capacity to induce immune responses in humans, a factor which should positively influence vector transduction efficiency while reducing the risk of any immune-associated  pathology .


AAV is not considered to have any known role in disease. [ 97 ]  However, host immune system response and immune tolerance reduce the efficacy of AAV-mediated gene therapy. Host immune response has been shown to respond to the AAV vectors, the transduced cells, and the transduced proteins. [ 98 ]  The immune response can be subdivided into two categories: innate and adaptive, the latter of which is divided into humoral and cell-mediated. [ 99 ] [ 100 ]


The  innate  immune response to the AAV vectors has been characterised in animal models. Intravenous administration in mice causes transient production of pro-inflammatory  cytokines  and some infiltration of  neutrophils  and other  leukocytes  into the liver, which seems to sequester a large percentage of the injected viral particles. Both soluble factor levels and cell infiltration appear to return to baseline within six hours. By contrast, more aggressive viruses produce innate responses lasting 24 hours or longer. [ 101 ]


In-vivo studies indicate that AAV vectors interact with the Toll-like receptor (TLR)9- and TLR2-MyD88 pathways to trigger the innate immune response by stimulating the production of interferons. [ 102 ]  It's shown that mice deficient in TLR9 are more receptive to AAV treatment and demonstrate higher levels of transgene expression [ 103 ]


Due to previous natural infection, many people have preexisting neutralizing antibodies (NAbs) against AAV's, which can significantly hinder its application in gene therapy. [ 104 ]  Even though AAV's are highly variable among wild-type and synthetic variants, antibody recognition sites may be conserved evolutionarily. [ 105 ]


The virus is known to instigate robust  humoral  immunity in animal models and in the human population, where up to 80% of individuals are thought to be  seropositive  for AAV2.  Antibodies  are known to be neutralising, and for gene therapy applications these do impact vector transduction efficiency via some routes of administration. As well as persistent AAV specific antibody levels, it appears from both prime-boost studies in animals and from clinical trials that the B-cell memory is also strong. [ 106 ]  In seropositive humans, circulating  IgG  antibodies for AAV2 appear to be primarily composed of the IgG1 and IgG2 subclasses, with little or no IgG3 or IgG4 present. [ 107 ]


The  cell-mediated  response to the virus and to vectors is poorly characterised, and has been largely ignored in the literature as recently as 2005. [ 106 ]  Clinical trials using an AAV2-based vector to treat haemophilia B seem to indicate that targeted destruction of transduced cells may be occurring. [ 108 ]  Combined with data that shows that  CD8+ T-cells  can recognise elements of the AAV capsid  in vitro , [ 109 ]  it appears that there may be a cytotoxic T lymphocyte response to AAV vectors. Cytotoxic responses would imply the involvement of  CD4+ T helper cells  in the response to AAV and  in vitro  data from human studies suggests that the virus may indeed induce such responses, including both Th1 and Th2 memory responses. [ 107 ]  A number of candidate T cell stimulating  epitopes  have been identified within the AAV capsid protein VP1, which may be attractive targets for modification of the capsid if the virus is to be used as a vector for gene therapy. [ 107 ] [ 108 ]


There are several steps in the AAV infection cycle, from infecting a cell to producing new infectious particles: [ citation needed ]


Some of these steps may look different in various types of cells, which, in part, contributes to the defined and quite limited native tropism of AAV. Replication of the virus can also vary in one cell type, depending on the cell's current  cell cycle  phase. [ 110 ]


The characteristic feature of the adeno-associated virus is a deficiency in replication and thus its inability to multiply in unaffected cells.  Adeno-associated virus spreads by co-infecting a cell with a helper virus. The first helper virus that was described as providing successful generation of new AAV particles, was the adenovirus, from which the AAV name originated. It was then shown that AAV replication can be facilitated by selected proteins derived from the adenovirus genome, [ 111 ] [ 112 ]  by other viruses such as HSV [ 113 ]  or vaccinia, or by genotoxic agents, such as  UV  irradiation or  hydroxyurea . [ 114 ] [ 115 ] [ 116 ]  Depending on the presence or absence of a helper virus, the life cycle of AAV follows either a lytic or lysogenic pathway, respectively. [ 117 ]  If there is a helper virus, AAV's gene expression activates, allowing the virus to replicate using the host cell's polymerase. When the helper virus kills the host cell, the new AAV virions are released. If there is not a helper virus present, AAV exhibits lysogenic behavior. When AAV infects a cell alone, its gene expression is repressed (AAV does not replicate), and its genome is incorporated into the host genome (into human chromosome 19). In rare cases, lysis can occur without a helper virus, but usually AAV can not replicate and kill a cell on its own. [ 118 ]


The minimal set of the adenoviral genes required for efficient generation, of progeny AAV particles, was discovered by Matsushita, Ellinger  et al. [ 111 ]  This discovery allowed for new production methods of recombinant AAV, which do not require adenoviral co-infection of the AAV-producing cells.  In the absence of helper virus or genotoxic factors, AAV DNA can either integrate into the host genome or persist in  episomal  form. In the former case integration is mediated by Rep78 and Rep68 proteins and requires the presence of ITRs flanking the region being integrated. In mice, the AAV genome has been observed persisting for long periods of time in quiescent tissues, such as skeletal muscles, in episomal form (a circular head-to-tail conformation). [ 119 ]


Alipogene tiparvovec , sold under the brand name  Glybera , is a  gene therapy  treatment designed to reverse  lipoprotein lipase deficiency  (LPLD), a rare recessive disorder, due to mutations in  LPL , which can cause severe  pancreatitis . [ 1 ]  It was recommended for approval by the  European Medicines Agency  in July 2012, and  approved  by the  European Commission  in November of the same year. It was the first marketing authorisation for a gene therapy treatment in either the European Union or the United States. [ 2 ] [ 3 ]


The medication is administered via a series of injections into the leg muscles. [ 4 ]


Glybera gained infamy as the "million-dollar drug" and proved commercially unsuccessful for a number of reasons. [ 4 ] [ 5 ]  Its cost to patients and payers, together with the rarity of LPLD, high maintenance costs to its manufacturer  uniQure , and failure to achieve approval in the US, led to uniQure withdrawing the drug after two years on the EU market. As of 2018, only 31 people worldwide have ever been administered Glybera, and uniQure has no plans to sell the drug in the US or Canada. [ 4 ] [ 5 ]


Glybera was developed over a period of decades by researchers at the  University of British Columbia (UBC) . [ 4 ]  In 1986,  Michael R. Hayden  and  John Kastelein  began research at UBC, confirming the hypothesis that LPLD was caused by a gene mutation. Years later, in 2002, Hayden and Colin Ross successfully performed gene therapy on test mice to treat LPLD; their findings were featured on the September 2004 cover of  Human Gene Therapy . Ross and Hayden next succeeded in treating cats in the same manner, with the help of Boyce Jones. [ 4 ]


Meanwhile, Kastelein—who had, by 1998, become an international expert in lipid disorders—co-founded Amsterdam Molecular Therapeutics (AMT), which acquired rights to Hayden's research with the aim of releasing the drug in Europe.


Since LPLD is a rare condition (prevalence worldwide 1–2 per million), related clinical tests and trials have involved unusually small cohort sizes. The first main trial (CT-AMT-011-01) involved just 14 subjects, [ 6 ]  and by 2015, a total of 27 individuals had been involved in phase III testing. [ 7 ]  The second phase of testing focused on subjects living along the  Saguenay River  in  Quebec , where LPLD affects people at the highest rate in the world (up to 200 per million) due to the  founder effect .


After over two years of testing, Glybera was approved in the European Union in 2012. [ 8 ]  However, after spending millions of euros on Glybera's approval, AMT went bankrupt and its assets were acquired by uniQure. [ 4 ]


Alipogene tiparvovec was expected to cost around  US$1.6 million  per treatment in 2012, [ 9 ] —revised to $1 million in 2015, [ 10 ] —making it the most expensive medicine in the world at the time. [ 11 ]  However,  replacement therapy , a similar treatment, can cost over $300,000 per year, for life. [ 4 ]


In 2015, uniQure dropped its plans for approval in the US and exclusively licensed rights to sell the drug in Europe to  Chiesi Farmaceutici  for  €31 million . [ 8 ] [ 4 ]


As of 2016, only one person had received the drug outside of a clinical trial. [ 8 ]


In April 2017, Chiesi quit selling Glybera and uniQure announced that it would not pursue the renewal of the marketing authorisation in the European Union when it was scheduled to expire that October, due to lack of demand. [ 12 ]  Afterwards, the three remaining doses in Chiesi's inventory were given away to two patients in  Germany  and one patient in  Italy  for  €1  each. [ 4 ]


The  adeno-associated virus  serotype 1 (AAV1) viral vector delivers an intact copy of the human  lipoprotein lipase  (LPL) gene to muscle cells. The LPL gene is not inserted into the cell's chromosomes but remains as free floating DNA in the nucleus. The injection is followed by  immunosuppressive therapy  to prevent immune reactions to the virus. [ 3 ]


Data from the clinical trials indicates that fat concentrations in blood were reduced between 3 and 12 weeks after injection, in nearly all patients. The advantages of AAV include apparent lack of pathogenicity, delivery to non-dividing cells, and much smaller risk of insertion [ 13 ]  compared to  retroviruses , which show random insertion with accompanying risk of  cancer . AAV also presents very low  immunogenicity , mainly restricted to generating neutralising  antibodies , and little well defined  cytotoxic response . [ 14 ] [ 15 ] [ 16 ]  The cloning capacity of the vector is limited to replacement of the virus's 4.8 kilobase genome.


The  Ames test  is a widely employed method that uses  bacteria  to test whether a given chemical can cause  mutations  in the  DNA  of the test organism. More formally, it is a  biological assay  to assess the  mutagenic  potential of chemical compounds. [ 1 ]  A positive test indicates that the chemical is mutagenic and therefore may act as a  carcinogen , because cancer is often linked to  mutation . The test serves as a quick and convenient assay to estimate the carcinogenic potential of a compound because standard carcinogen assays on mice and rats are time-consuming (taking two to three years to complete) and expensive. However, false-positives and false-negatives are known. [ 2 ]


The procedure was described in a series of papers in the early 1970s by  Bruce Ames  and his group at the  University of California, Berkeley . [ 3 ] [ 4 ] [ 5 ] [ 6 ]


The Ames test uses several strains of the bacterium  Salmonella typhimurium  that carry mutations in genes involved in  histidine  synthesis. These strains are  auxotrophic  mutants, i.e. they require histidine for growth, but cannot produce it. The method tests the capability of the tested substance in creating mutations that result in a return to a "prototrophic" state, so that the cells can grow on a histidine-free medium.


The tester strains are specially constructed to detect either  frameshift  (e.g. strains TA-1537 and TA-1538) or  point  (e.g. strain TA-1531)  mutations  in the genes required to synthesize histidine, so that mutagens acting via different mechanisms may be identified. Some compounds are quite specific, causing reversions in just one or two strains. [ 4 ]  The tester strains also carry mutations in the genes responsible for  lipopolysaccharide  synthesis, making the  cell wall  of the bacteria more permeable, [ 5 ]  and in the  excision repair system  to make the test more sensitive. [ 6 ]


Larger organisms like mammals have metabolic processes that could potentially turn a chemical considered not mutagenic into one that is or one that is considered mutagenic into one that is not. [ 7 ]  Therefore, to more effectively test a chemical compound's mutagenicity in relation to larger organisms, rat liver enzymes can be added in an attempt to replicate the metabolic processes' effect on the compound being tested in the Ames Test. Rat liver extract is optionally added to simulate the effect of  metabolism , as some compounds, like  benzo[ a ]pyrene , are not mutagenic themselves but their metabolic products are. [ 3 ]


The bacteria are spread on an  agar  plate with a small amount of histidine. This small amount of histidine in the growth medium allows the bacteria to grow for an initial time and have the opportunity to mutate.
When the histidine is depleted only bacteria that have mutated to gain the ability to produce its own histidine will survive. The plate is incubated for 48 hours. The mutagenicity of a substance is proportional to the number of colonies observed.


Mutagens identified via Ames test are also possible carcinogens, and early studies by Ames showed that 90% of known carcinogens may be identified via this test. [ 8 ]   Later studies however showed identification of 50–70% of known carcinogens. [ citation needed ]   The test was used to identify a number of compounds previously used in commercial products as potential carcinogens. [ 9 ]   Examples include  tris(2,3-dibromopropyl)phosphate , which was used as a flame retardant in plastic and textiles such as children's sleepwear, [ 10 ]  and  furylfuramide  which was used as an antibacterial additive in food in Japan in the 1960s and 1970s.  Furylfuramide in fact had previously passed animal tests, but more vigorous tests after its identification in the Ames test showed it to be carcinogenic. [ 11 ]   Their positive tests resulted in those chemicals being withdrawn from use in consumer products.


One interesting result from the Ames test is that the dose response curve using varying concentrations of the chemical is almost always linear, [ 8 ]  indicating that there is no threshold concentration for mutagenesis. It therefore suggests that, as with radiation, there may be  no safe threshold  for chemical mutagens or carcinogens. [ 12 ] [ 13 ]   However, some have proposed that organisms could tolerate low levels of mutagens due to protective mechanisms such as  DNA repair , and thus a threshold may exist for certain chemical mutagens. [ 14 ]   Bruce Ames himself argued against linear dose-response extrapolation from the high dose used in carcinogenesis tests in animal systems to the lower dose of chemicals normally encountered in human exposure, as the results may be false positives due to  mitogenic  response caused by the artificially high dose of chemicals used in such tests. [ 15 ] [ 16 ]   He also cautioned against the "hysteria over tiny traces of chemicals that may or may not cause cancer", that "completely drives out the major risks you should be aware of". [ 17 ]


The Ames test is often used as one of the initial screens for potential drugs to weed out possible carcinogens, and it is one of the eight tests required under the  Pesticide Act  (USA) and one of the six tests required under the  Toxic Substances Control Act  (USA). [ 18 ]


Salmonella typhimurium  is a prokaryote, therefore it is not a perfect model for humans.  Rat liver  S9 fraction  is used to mimic the mammalian metabolic conditions so that the mutagenic potential of metabolites formed by a parent molecule in the hepatic system can be assessed; however, there are differences in metabolism between humans and rats that can affect the mutagenicity of the chemicals being tested. [ 19 ]   The test may therefore be improved by the use of human liver S9 fraction; its use was previously limited by its availability, but it is now available commercially and therefore may be more feasible. [ 20 ]   An adapted  in vitro  model has been made for eukaryotic cells, for example yeast.


Mutagens identified in the Ames test need not necessarily be carcinogenic, and further tests are required for any potential carcinogen identified in the test.  Drugs that contain the nitrate moiety sometimes come back positive for Ames when they are indeed safe.  The nitrate compounds may generate  nitric oxide , an important signal molecule that can give a false positive.   Nitroglycerin  is an example that gives a positive Ames yet is still used in treatment today.  Nitrates in food however may be reduced by bacterial action to nitrites which are known to generate carcinogens by reacting with amines and amides.  Long toxicology and outcome studies are needed with such compounds to disprove a positive Ames test.


The Ames test was initially developed using agar plates (the plate incorporation technique), as described above. Since that time, an alternative to performing the Ames test has been developed, which is known as the "fluctuation method". This technique is the same in concept as the agar-based method, with bacteria being added to a reaction mixture with a small amount of  histidine , which allows the bacteria to grow and mutate, returning to synthesize their own histidine. By including a pH indicator, the frequency of mutation is counted in  microplates  as the number of wells which have changed color (caused by a drop in pH due to metabolic processes of reproducing bacteria). As with the traditional Ames test, the sample is compared to the natural background rate of reverse mutation in order to establish the genotoxicity of a substance. The fluctuation method is performed entirely in liquid culture and is scored by counting the number of wells that turn yellow from purple in 96-well or 384-well microplates.


In the 96-well plate method the frequency of mutation is counted as the number of wells out of 96 which have changed color. The plates are incubated for up to five days, with mutated (yellow) colonies being counted each day and compared to the background rate of reverse mutation using established tables of significance to determine the significant differences between the background rate of mutation and that for the tested samples.


In the more scaled-down 384-well plate microfluctuation method the frequency of mutation is counted as the number of wells out of 48 which have changed color after 2 days of incubation. A test sample is assayed across 6 dose levels with concurrent zero-dose (background) and positive controls which all fit into one 384-well plate. The assay is performed in triplicates to provide statistical robustness. It uses the recommended OECD Guideline 471 tester strains (histidine auxotrophs and tryptophan auxotrophs).


The fluctuation method is comparable to the traditional pour plate method in terms of sensitivity and accuracy, however, it does have a number of advantages: it needs less test sample, it has a simple colorimetric endpoint, counting the number of positive wells out of possible 96 or 48 wells is much less time-consuming than counting individual colonies on an agar plate. Several commercial kits are available. Most kits have consumable components in a ready-to-use state, including lyophilized bacteria, and tests can be performed using multichannel pipettes. The fluctuation method also allows for testing higher volumes of aqueous samples (up to 75% v/v), increasing the sensitivity and extending its application to low-level environmental mutagens. [ 21 ]


In  population genetics , an  ancestry-informative marker  ( AIM ) is a  single-nucleotide polymorphism  that exhibits substantially different frequencies between different populations. A set of many AIMs can be used to estimate the proportion of ancestry of an individual derived from each population.


A single-nucleotide polymorphism is a modification of a single nucleotide base within a DNA sequence. [ 1 ]  There are an estimated 15 million SNP ( Single-nucleotide polymorphism ) sites  (out of roughly 3 billion base pairs, or about 0.4%)   from among which AIMs may potentially be selected. [ 2 ]  The SNPs that relate to ancestry are often traced to the Y chromosome and  mitochondrial DNA  because both of these areas are inherited from one parent, eradicating complexities that come with parental gene recombination. [ 3 ] [ page needed ]  SNP mutations are rare, so sequences with SNPs tend to be passed down through generations rather than altered each generation. However, because any given SNP is relatively common in a population, analysts must examine groups of SNPs (otherwise known as AIMS) to determine someone's ancestry. Using statistical methods such as apparent error rate and Improved Bayesian Estimate, the set of SNPs with the highest accuracy for predicting a specific ancestry can be found. [ 4 ]


Examining a suite of these markers more or less evenly spaced across the genome is also a cost-effective way to discover novel genes underlying complex diseases in a technique called  admixture mapping  or mapping by admixture  linkage disequilibrium .


As one example, the  Duffy  Null  allele  (FY*0) has a frequency of almost 100% of Sub-Saharan Africans, but occurs very infrequently in populations outside of this region.  A person having this allele is thus more likely to have Sub-Saharan African ancestors. North and South  Han Chinese  ancestry can be distinguished unambiguously using a set of 140 AIMS. [ 5 ]


Collections of AIMs have been developed that can estimate the geographical origins of ancestors from within Europe. [ 6 ]


Following the development of ancient DNA databases, ancient ancestry-informative marker (aAIM) were similarly defined as a  single-nucleotide polymorphism  that exhibits substantially different frequencies between different ancient populations. A set of aAIMs can be used to identify the ancestry of ancient populations and eventually quantify the genetic similarity to modern-day individuals. [ 7 ]


The discovery of ancestry-informative markers was made possible by the development of  next generation sequencing , or NGS. NGS enables the study of genetic markers by isolating specific  gene sequences . [ 8 ]  One such method for sequence extraction is the use  restriction enzymes , specifically  endonuclease , which modifies the DNA sequence. This enzyme can be used with DNA ligase (connecting two different DNA), modifying  DNA by inserting DNA from other organism. [ 9 ]  Another method, cDNA sequencing, or  RNA-seq , can also help to acquire information of the  transcriptomes  in a broad range of organisms and find SNPs ( single nucleotide polymorphisms ), within a DNA sequence.


Ancestry informative markers have a number of applications in genetic research, forensics, and private industry. AIMs that indicate a predisposition for diseases such as  type 2 diabetes  mellitus and  renal disease  have been shown to reduce the effects of  genetic admixture  in ancestral mapping when using admixture mapping software. [ 10 ]  The differential ability of ancestry-informative markers allows scientists and researchers to narrow geographical populations of concern; for example, illegal  organ trafficking  can be traced to certain areas by comparing the samples taken from organ recipients and deciphering the foreign marker in their body. [ 11 ]  An array of private companies, such as  23andMe  and  AncestryDNA , provide cost-effective  direct-to-consumers (DTC)   genetic testing  by analyzing ancestry informative markers to determine geographic origins. These private companies collect massive quantities of data such as biological samples and self-reported information from consumers, a practice known as  biobank ing, enabling their researchers to discover more insights on AIMs. [ 12 ]


Though AIM panels can be useful for disease screening, the  Genetic Information Nondiscrimination Act  (GINA) prevents the use of genetic information for insurance and workplace discrimination. [ 13 ]


Different ancestral traits and their affiliation to diseases can help scientists determine appropriate approaches of treatment for a specific population. [ 14 ]  Medical researchers have revealed the link between ancestry traits and some common diseases; for example, individuals of African descent have been found to be at higher risk of  asthma  than those of European ancestry. [ 15 ]


AIM panels can be used for detecting disease  risk factors . One such panel was created for  African American  ancestry based on subsets of commercially available SNP arrays. These types of arrays can help reduce the cost of identifying risk factors, since they allow researchers to screen for ancestry markers instead of the entire genome. This is due to the fact that these SNP arrays narrow the scope of the necessary screening from hundreds of thousands of SNP markers to a panel of a few thousands of AIMs. [ 16 ]


While some believe that structured populations should be used in studies to better ascertain genetic associations to  diseases , the social implications of the potential racial stigma that may result from such studies is a major concern. However, the study done by Yang et al. (2005) suggests that the technology to conduct deeper research into and identify ancestry-associated variations in human disease does already exist. [ 14 ]


Ancestry.com LLC  is an American  genealogy  company based in  Lehi, Utah . The largest  for-profit  genealogy company in the world, it operates a network of genealogical, historical records, and related  genetic genealogy  websites. It is owned by  The Blackstone Group , which acquired the company on December 4, 2020, in a deal valued at $4.7 billion. [ 7 ] [ 8 ] [ 9 ]


As of 2022, the company said it had provided access to 30 billion historical records, tripling its November 2018 figure of 10 billion records. [ 10 ] [ 11 ]  In 2018 it also reported having 3 million paying subscribers, and to have sold 18 million  DNA kits  to customers. [ 11 ]  By 2023, Ancestry was the largest provider of consumer DNA testing in the world with a network of over 25 million users, [ 12 ]  and Ancestry DNA testing is now available in 128 countries.


As well as its main website, Ancestry operates country-specific versions for Australia, Canada, France, Germany, Italy, Mexico, Sweden and the United Kingdom. [ 13 ]


Ancestry Publishing was founded in 1983, producing genealogical data in print form, with more than 40 family history magazine titles and genealogy reference books published. [ 14 ] [ 15 ]


In 1990, Paul Brent Allen and Dan Taggart, two  Brigham Young University  graduates, founded Infobases and began offering  Latter-day Saints  (LDS) publications on  floppy disks . In 1988, Allen had worked at  Folio Corporation , founded by his brother Curt and his brother-in-law  Brad Pelo .
The service was initially to help members of the church to research their ancestors.


Infobases' first products were  floppy disks  and  compact disks  sold from the back seat of the founders' car. In 1994, Infobases was named among  Inc.  magazine's 500 fastest-growing companies. [ 16 ]  Their first offering on  CD  was the LDS Collectors Edition, released in April 1995, selling for $299.95, [ 17 ]  which was offered in an online version in August 1995. [ 18 ]  Ancestry officially went online with the launch of Ancestry.com in 1996. [ 15 ]


On January 1, 1997, Infobases' parent company, Western Standard Publishing, purchased Ancestry, Inc., [ 19 ]  publisher of  Ancestry  magazine and genealogy books. Western Standard Publishing's CEO was  Joseph A. Cannon , one of the principal owners of  Geneva Steel . [ 20 ]


In July 1997, Allen and Taggart purchased Western Standard's interest in Ancestry, Inc. At the time,  Brad Pelo  was  president  and CEO of Infobases, and president of Western Standard. Less than six months earlier, he had been president of Folio Corporation, whose digital technology Infobases was using. In March 1997, Folio was sold to  Open Market  for $45 million. [ 21 ]  The first public evidence of the change in ownership of  Ancestry  magazine came with the July/August 1997 issue, which showed a newly reorganized Ancestry, Inc., as its publisher. That issue's masthead also included the first use of the Ancestry.com web address.


More growth for Infobases occurred in July 1997, when Ancestry, Inc. purchased  Bookcraft, Inc. , a publisher of books written by leaders and officers of the LDS Church. [ 22 ] [ 23 ]  Infobases had published many of Bookcraft's books as part of its LDS Collector's Library. Pelo also announced that Ancestry's product line would be greatly expanded in both CDs and online.  Alan Ashton , a longtime investor in Infobases and founder of  WordPerfect , was its chairman of the board.


Allen and Taggart began running Ancestry, Inc. independently from Infobases in July 1997, and began creating one of the largest online subscription-based genealogy database services. [ 24 ]


In April 1999, to better focus on its Ancestry.com and MyFamily.com Internet businesses, Infobases sold the Bookcraft brand name and its catalog of print books to its major competitor in the LDS book market,  Deseret Book . Included in the sale were the rights to Infobases' LDS Collectors Library on CD. A year earlier, Deseret Book had released a competing product called GospeLink, and the two products were combined as a single product by Deseret Book. [ 25 ] [ 26 ]


The MyFamily.com website launched in December 1998, with additional free sites beginning in March 1999. [ 27 ]  The site generated one-million registered users within its first 140 days. [ 24 ]  The company raised more than US$90 million in venture capital from investors [ 24 ]  and changed its name on November 17, 1999, from Ancestry.com, Inc. to MyFamily.com, Inc. Its three Internet genealogy sites were then called Ancestry.com, FamilyHistory.com, and MyFamily.com. [ 28 ]  Sales were about US$62 million for 2002 and US$99 million for 2003. [ 29 ]


In March 2004, the company, which had outgrown its call center in  Orem, Utah , opened a new  call center , which accommodated about 700 agents at a time, in  Provo . [ 30 ]   Heritage Makers  was acquired by MyFamily.com in September 2005. [ 31 ]


On November 5, 2009, Ancestry.com became a publicly traded company on  NASDAQ  (symbol: ACOM), with an initial public offering of 7.4 million shares priced at $13.50 per share, underwritten by  Morgan Stanley ,  Bank of America ,  Merrill Lynch ,  Jefferies & Company ,  Piper Jaffray , and  BMO Capital Markets . [ 32 ]


In 2010, Ancestry sold its book publishing assets to  Turner Publishing Company . [ 33 ]


In 2010, Ancestry.com expanded its domestic operations with the opening of an office in  San Francisco, California , staffed with brand new engineering, product, and marketing teams geared toward developing some of Ancestry's cutting-edge technology and services. In 2011, Ancestry launched an  Android  and  iOS  app. [ 34 ] [ 35 ]


In December 2011, Ancestry.com moved the  Social Security Death Index  search behind a  paywall  and stopped displaying the Social Security information of people who had died within the past 10 years, because of  identity theft  concerns. [ 36 ]


In March 2012, Ancestry.com acquired the collection of DNA assets from  GeneTree . [ 37 ]


In September 2012, Ancestry.com expanded its international operations with the opening of its European headquarters in  Dublin, Ireland . The Dublin office includes a new call center for international customers, as well as product, marketing, and engineering teams. [ 38 ] [ 39 ]


In October 2012, Ancestry.com agreed to be acquired by a private equity group consisting of  Permira  Advisers LLP, members of Ancestry.com's management team, including CEO Tim Sullivan and CFO Howard Hochhauser, and Spectrum Equity, for $32 per share or around $1.6 billion. [ 40 ]  At the same time, Ancestry.com purchased a photo digitization and sharing service called  1000Memories . [ 41 ]


In 2013, Ancestry acquired  Find a Grave  from Jim Tipton, who had created the original site in 1995.  Ancestry subsequently launched a redesigned version of Find a Grave in 2017.


On July 16, 2015, Ancestry launched AncestryHealth, and announced the appointment of Cathy A. Petti as its Chief Health Officer. [ 42 ]  That year, Ancestry partnered with the  Google  subsidiary,  Calico , to focus on longevity research and therapeutics, in an effort to investigate human heredity of lifespan. [ 43 ] [ 44 ]


In April 2016,  GIC Private Limited  (a sovereign wealth fund owned by the Government of Singapore) and  Silver Lake  (a private equity fund manager) bought equity stakes in Ancestry.com. [ 45 ]  The estimated market value of Ancestry.com in 2017 was more than $3 billion. [ 46 ]


In June 2017, Ancestry.com stated that it was migrating all of its applications and data to  Amazon Web Services  (AWS). [ 47 ] [ 48 ]


Through vintage photographs, a woman was able to document eight generations of her family, dating back to 1805, including an interracial couple. [ 49 ]  A controversial Ancestry.com advertisement had run on television stations in  Utah , showing a slavery-era interracial couple. The advertisement was criticized by a news correspondent for Boston radio station  WBUR-FM  and  MSNBC , and law professor  Melissa Murray , on the grounds that it romanticized slavery in the  antebellum South . In April 2019, Ancestry withdrew the advertisement with an apology. [ 50 ]


In November 2018, Ancestry claimed to have over 10 billion digitized records and over three-million paying customers. [ 51 ]


In December 2018, after authorities arrested the  Golden State Killer  and used  GEDmatch  to solve the case, Ancestry.com and  23andMe  announced a data policy that they would not allow their DNA profiles to be used for crime solving without a valid legal process such as a  search warrant , as they believe it violates users' privacy. [ 52 ] [ 53 ]  In the 2021 case of the  murder of George Seitz , Ancestry.com was used to help identify the remains of a crime victim. [ 54 ]


In August 2020,  The Blackstone Group  announced plans to acquire Ancestry for $4.7 billion, [ 7 ]  and in December 2020 the acquisition occurred.


In February 2021, Ancestry announced  Deb Liu , a former Facebook executive, as their CEO effective March 1. [ 1 ]


In November 2021, Ancestry announced the acquisition of French Genealogy Company  Geneanet . [ 55 ]


In March 2023, Ancestry announced that it had won a contract to digitize over 3 million British Army service records, which it would release from 2024 through 2029. In February 2021 the Ministry Of Defence commenced transferring 9.7 million military records for individuals with a discharge date before 31 December 1963 to The National Archives UK, its largest record transfer in the history of the organization. [ 56 ]


AncestryDNA is a subsidiary of Ancestry LLC. AncestryDNA offers a direct-to-consumer  genealogical DNA test . [ 57 ]  Consumers provide a sample of their DNA to the company for analysis. AncestryDNA then uses DNA sequences to infer family relationships with other Ancestry DNA users, and to infer "ancestral regions" [ 58 ]  (previously " ethnicity  estimates"). [ 59 ]  Previously, Ancestry.com also offered paternal  Y-chromosome DNA  and maternal  mitochondrial DNA  tests, but those were discontinued in June 2014. [ 60 ]  The company describes the technical process of testing in a series of scientific  white papers . [ 61 ]  In July 2020, the company claimed that their database contained 18 million completed DNA kits bought by customers. [ 62 ] [ 51 ] [ 63 ]


Ancestry DNA is commonly used for  donor conceived persons  to find their biological siblings and in some cases their  sperm  or  egg donor . [ 64 ]


The testing itself is performed by  Quest Diagnostics . [ 65 ]


AncestryDNA offers the option to participate in their Human Diversity Project, a "scientific research project aimed at helping scientists better understand population history, population movements, and human health". [ 66 ] [ 67 ]


Members can also pay an additional fee to access DNA traits, which range from predicted physical traits to limited health data.


Since 2023, Ancestry has also offered genetic testing for pets, which at the moment is limited to dogs. [ 3 ]  The test compares the DNA to over 400 breeds.


On September 30, 2013, Ancestry.com announced its acquisition of  Find a Grave . Site editor Jim Tipton said of the purchase that Ancestry.com had "been linking and driving traffic to the site for several years. Burial information is a wonderful source for people researching their family history". Ancestry.com launched a mobile app in March 2014. [ 68 ]


Fold3 is a premium portal that specializes in military genealogy. Subscribers access an online database with military records, including stories, photos, and personal documents. It was rebranded as Forces War Records in the  British & Commonwealth  nations in April 2023. [ 69 ]


The website also features the  Guion Miller Roll , an  Eastern Cherokee  tribal roll. [ 70 ]


Ancestry.com acquired  iArchives, Inc. , and its service footnote.com, in 2010. The purchase brought in assets including processes for digitizing  microfilm . [ 71 ] [ 72 ]  Footnote was rebranded Fold3 in 2011. [ 73 ]


On August 31, 2021, Ancestry.com announced its acquisition of  Geneanet . Geneanet explains that the acquisition by Ancestry is the consequence of the failure of the Filae negotiations with the birth of a formidable competitor. The Geneanet.org site, which must remain autonomous, indicates that it will give access to many databases indexed by Ancestry within the framework of Premium subscriptions. [ 74 ]


Archives.com was bought by Ancestry for $100 million in 2012. [ 75 ]  Archives.com is a genealogy website specializing in census and vital records. As of November 29, 2023, Archives.com claimed 11.8 billion photos, newspapers, census, and vital records in its collections. [ 76 ]


In 2012, Ancestry spun off its digitized online newspaper components into a standalone service, Newspapers.com. [ 77 ]  By 2024, the site had over 25,000 newspapers able to be searched, including some from ten different countries.


The Web site's principal competitor is  NewspaperArchive , which claims it has online newspapers dating from 1607 worldwide, and its index in March 2024 included over 16,000 newspapers. [ 78 ]  Both websites have similar models for increasing their databases: striking deals with libraries, publishers and historical organizations to scan the publications for free to include in their database. Some participants see the process of free scanning as an easier, cheaper and quicker way to get their publications online than working through the U.S. government-operated  National Digital Newspaper Program . [ 79 ] [ 80 ]


RootsWeb, acquired by Ancestry in June 2000, is a free genealogy community that uses online forums, mailing lists, and other resources to help people research their family history. Users can upload  GEDCOM  files of their information for others to search at the WorldConnect portion of the site. Trees uploaded to WorldConnect are searchable at both the RootsWeb and Ancestry Web sites.


On December 20, 2017, a file containing 300,000 RootsWeb user names, passwords, and email addresses was exposed to the Internet. The 300,000 records were from RootsWeb surname list service; 55,000 of those records were also Ancestry.com login credentials. [ 81 ]  By 2024, the hosted Web sites were all read-only, disabling all user logins.


We Remember is a free online memorial platform, [ 82 ]  which was launched by Ancestry in November 2017. [ 83 ] [ 84 ]  It allows users to create a space to preserve and share photos and videos about the deceased. [ 85 ]


Forces War Records was a low cost provider of transcribed genealogical data from British sources. The irony was that much of the content behind their paywall had simply been taken from public domain sources. As a consequence, there was a lack of transparency as to where they sourced their content from. [ 86 ] [ 87 ]  (See  Wikipedia:Reliable sources/Noticeboard/Archive 315#RfC: forces-war-records.co.uk ) They came under criticism for difficulties in canceling subscriptions, with a complaint about their misleading marketing being upheld by the Advertising Standards Authority. [ 88 ]


Acquired by Ancestry on May 24, 2021, the press release announced that 'Forces War Records is a British military genealogy-specialist website with a unique product that helps people both discover and contextualize their family's military history.' [ 89 ]  Given that Fold3 had a negative perception as "US-centric", [ 90 ]  the same dataset offerings and web architecture were used in the UK, albeit branded as Forces War Records, from April 2023 onwards. [ 69 ]  The provision of service records for the first time ever, via this brand, as a consequence of the linkage with fold3, has reinvigorated the brand. Not only transcriptions, but also images of source documents are now available to the subscriber. [ 91 ]  In support of the brand being relaunched as a premium portal that specializes in military genealogy, half a million records were added to the (FWR/Fold3) portal in July 2023. [ 92 ]


Antisense therapy  is a form of treatment that uses antisense  oligonucleotides  (ASOs) to target  messenger RNA  (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including  ribonuclease H  mediated decay of the pre-mRNA, direct steric blockage, and  exon  content modulation through  splicing  site binding on pre-mRNA. [ 1 ]  Several ASOs have been approved in the United States, the European Union, and elsewhere.


The common stem for antisense oligonucleotides drugs is -rsen. The substem -virsen designates antiviral antisense oligonucleotides. [ 2 ]


Developments in ASO modification are separated into three generations. [ 3 ]  Generation one is called backbone-modified and focuses on the phosphodiester group of the nucleotide. This impacts inter-nucleotide binding. These modifications led to better distribution, reduced urinary excretion, and prolonged residence time of the ASOs in the cell. Some examples of first generation modifications include the addition of a phosphorothioate group (PS), methyl group, or nitrogen. The most common is the phosphorothioate group (PS) in which the oxygen atoms of a phosphodiester group are replaced with sulfur atoms, greatly improving efficacy and reducing degradation. Generation two is sugar-modified, focused on the ribose sugar of the nucleotide. This generation saw improved binding affinity while reducing degradation. Some examples of generation two modifications are the substitution of R group with morpholine group (MO) and the usage of phosphorodiamidate morpholino oligomer (PMO) and thiomorpholine oligomer (TMO) as linkages between the ribose sugar and phosphodiester group in the backbone. Generation three is nucleobase-modified, the least common type of modification. These modifications enhanced binding affinity and cell penetration while reducing degradation and off-target effects. Examples include the introduction of G-clamps, pseudoisocytosine, and the substitution of bases with amine, thione, halogen, alkyl, alkenyl, or alkynyl groups. [ 4 ]


ASO-based drugs employ highly modified, single-stranded chains of synthetic  nucleic acids  that achieve wide tissue distribution with very long half-lives. [ 5 ] [ 6 ] [ 7 ]  For instance, many ASO-based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit  nuclease  degradation enabling vehicle-free delivery to cells. [ 8 ] [ 9 ]


Phosphorothioate ASOs can be delivered to cells without the need of a delivery vehicle. ASOs do not penetrate the  blood brain barrier  when delivered systemically but they can distribute across the  neuraxis  if injected in the  cerebrospinal fluid  typically by  intrathecal administration . Newer formulations using conjugated ligands greatly enhances delivery efficiency and cell-type specific targeting. [ 8 ]


Tofersen  (marketed as Qalsody) was approved by the FDA for the treatment of  SOD1- associated   amyotrophic lateral sclerosis  (ALS) in 2023. [ 10 ]  It was developed by Biogen under a licensing agreement with Ionis Pharmaceuticals. In trials the drug was found to lower levels of an ALS biomarker, neurofilament light change, and in long-term trial extensions to slow disease. [ 10 ]  Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence. [ 11 ]


Milasen is a novel individualized therapeutic agent that was designed and approved by the FDA for the treatment of  Batten disease . This therapy serves as an example of personalized medicine. [ 12 ] [ 13 ]


In 2019, a report was published detailing the development of milasen, an antisense oligonucleotide drug for  Batten disease , under an expanded-access investigational clinical protocol authorized by the  Food and Drug Administration  (FDA). [ 12 ]  Milasen "itself remains an investigational drug, and it is not suited for the treatment of other patients with Batten's disease" because it was customized for a single patient's specific mutation. [ 12 ]  However it is an example of  individualized genomic medicine  therapeutical intervention. [ 12 ] [ 14 ]


Fomivirsen  (marketed as Vitravene), was approved by the U.S. FDA in August 1998, as a treatment for  cytomegalovirus retinitis . [ 15 ]


Several  morpholino  oligos have been approved to treat specific groups of mutations causing  Duchenne muscular dystrophy . In September 2016,  eteplirsen  (ExonDys51) received FDA approval [ 16 ]  for the treatment of cases that can benefit from skipping exon 51 of the dystrophin transcript. In December 2019,  golodirsen  (Vyondys 53) received FDA approval [ 17 ]  for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript. In August 2020,  viltolarsen  (Viltepso) received FDA approval for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript. [ 18 ]


Volanesorsen  was approved by the  European Medicines Agency  (EMA) for the treatment of  familial chylomicronaemia syndrome  in May 2019. [ 19 ] [ 20 ]


In January 2013  mipomersen  (marketed as Kynamro) was approved by the FDA for the treatment of homozygous  familial hypercholesterolemia .
 [ 21 ] [ 22 ] [ 23 ]


Inotersen  received FDA approval for the treatment of  hereditary transthyretin-mediated amyloidosis  in October 2018. [ 24 ]  The application for inotersen was granted  orphan drug  designation. [ 24 ]  It was developed by Ionis Pharmaceuticals and licensed to  Akcea Therapeutics .  Patisiran  (sold under Onpattro) was developed by  Alnylam Pharmaceuticals , and also approved for use in the US and EU in 2018 with orphan drug designation. [ 25 ]  Its mechanism-of-action is the  active substance  of  small interfering RNA (siRNA) , which allows it to interfere with and block the production of  trasnthyretin . [ 26 ]  As such, it was the first FDA-approved siRNA therapeutic. [ 25 ]


In 2004, development of an antisense therapy for  spinal muscular atrophy  began. Over the following years, an  antisense oligonucleotide  later named  nusinersen  was developed by  Ionis Pharmaceuticals  under a licensing agreement with  Biogen . In December 2016, nusinersen received regulatory approval from  FDA [ 27 ] [ 28 ]  and soon after, from other regulatory agencies worldwide.


As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in  advanced clinical trials  (phase II or III). [ 29 ] [ 30 ]


A follow-on drug to Inotersen is being developed by Ionis Pharmaceuticals and under license to  Akcea Therapeutics  for hereditary transthyretin-mediated amyloidosis. In this formulation the ASO is conjugated to  N-Acetylgalactosamine  enabling hepatocyte-specific delivery, greatly reducing dose requirements and side effect profile while increasing the level of  transthyretin  reduction in patients.


Tominersen (also known as IONIS-HTT Rx  and RG6042) was tested in a phase 3 trial for  Huntington's disease [ 31 ]  although this trial was discontinued on March 21, 2021, due to lack of efficacy. [ 32 ]  It is currently licensed to  Roche  by Ionis Pharmaceuticals.


Clinical trials are ongoing for several diseases and conditions including: