Author Interviews, Breast Cancer, Genetic Research, JAMA, Race/Ethnic Diversity / 22.01.2021 Interview with: Kent Hoskins, MD Eileen Lindsay Heidrick Professor in Oncology Division of Hematology/Oncology University of Illinois at Chicago Director of Cancer Genetics Co-Leader, Breast Cancer Research Group University of Illinois Cancer Center What is the background for this study? Response: The racial disparity in breast cancer mortality emerged in the US in the late 1980s in the wake of widespread implementation of mammography screening and the development of successful systemic adjuvant therapies for early breast cancer. Unfortunately, more than three decades later, Black women in the US still have a 40% higher mortality rate from breast cancer compared with non-Hispanic White women despite similar disease incidence. Health disparities research has primarily focused on the fact that Black women have a higher incidence of the aggressive triple-negative subtype, and that they are more likely to present with more advanced stages of disease. As important as those factors are, in recent years our group and others reported that Black women with hormone receptor-positive breast cancer have worse survival than non-Hispanic white women even after adjustment for stage at diagnosis and treatment. Since nearly 2/3 of breast cancers in Black women are hormone receptor-positive, this is a significant contributor to the overall mortality disparity. Importantly, these studies also suggested that Black women disproportionately develop biologically aggressive forms of hormone-dependent breast cancer, which is typically considered a more favorable disease subtype. Using data on more than 70,000 patients from the SEER registry that is linked to data from Genomic Health Laboratory, which provides the Oncotype DX recurrence score (the most commonly ordered prognostic/predictive multi-gene expression assay for early breast cancer), we set out to address three questions: 1) is there evidence of disproportionately aggressive tumor biology among Black women with hormone receptor (HR)-positive breast cancer, as reflected in the Oncotype DX recurrence score? 2) Is there a racial survival disparity even among patients with early stage, axillary node-negative tumors with comparable recurrence scores on the Oncotype assay? and 3) Is there is a difference in the prognostic accuracy of the Oncotype assay between Black and non-Hispanic white patients, since there was limited representation of Black women in the development and validation of the Oncotype assay and other prognostic/predictive assays?  (more…)
Author Interviews, Autism, Fertility, Genetic Research / 12.01.2021 Interview with: Michael Skinner,  PhD Eastlick Distinguished Professor Founding Director, Center for Reproductive Biology School of Biological Sciences Washington State University Pullman WA What is the background for this study? Response: Over twenty years ago we identified the existence of a non-genetic form of inheritance through analysis of environmentally induced epigenetic transgenerational inheritance of disease, now well established in a number of species including humans.  I was giving a talk on this topic at a meeting in Spain.   This study was initiated following the scientific meeting in Spain with an in vitro fertilization clinical group that said they had access to sperm from males with and without autistic children.  It took several years to collect and characterize the samples, and find financial support for the study.  Once this was done then we did the molecular analysis to see if the sperm from fathers with autistic children had epigenetic, DNA methylation alterations, that associated with them having offspring with autism. (more…)
Author Interviews, COVID -19 Coronavirus, Genetic Research, NYU / 19.12.2020 Interview with: John T. Poirier, PhD Assistant Professor of Medicine, NYU Grossman School of Medicine Director, Preclinical Therapeutics Program Perlmutter Cancer Center An NCI-designated Comprehensive Cancer Center NYU Langone Health Smilow Research Center New York, NY 10016 What is the background for this study? Response: The goal of this study was to identify in as much detail as possible the genes that SARS-CoV-2, the virus that causes COVID-19, needs to successfully infect a human host cell. CRISPR technology played a key role in this research; it was used to disrupt every gene in the human genome in parallel and study which ones were required for infection. (more…)
Author Interviews, Genetic Research, Orthopedics / 18.12.2020 Interview with: Karin Magnusson PT, PhD Associate Researcher Lund University and Norwegian Institute of Public Health What is the background for this study? Response: Anterior cruciate ligament (ACL) injury is one of the most common knee injuries, for which very limited data has been presented on the genetic contribution. Based on our knowledge of the role of genetics in the development of ACL-rupture related traits, such as joint hypermobility and knee osteoarthritis, we hypothesized that heritability might play a role also in ACL injury. Using the Swedish Twin Registry, which is the world's largest twin registry and in this study including more than 88.000 twins, we had unique data to for the first time reliably estimate the heritability for this common knee injury.  (more…)
Alzheimer's - Dementia, Author Interviews, Cognitive Issues, Genetic Research, Nutrition / 11.12.2020 Interview with: Auriel Willette, PhD Assistant Professor Food Science and Human Nutrition Iowa State University What is the background for this study? Response: To date, pharmacology therapies done to slow down or halt Alzheimer's disease have been inconclusive. Lifestyle interventions like changes in diet and activity are also mixed but do show some promise. Dietary clinical trials or self-reported diet have tended to focus on groups of foods such as the Mediterranean or MIND diet. To build from this excellent work, we were curious if we could pinpoint specific foods that were correlated with changes in fluid intelligence over time. Fluid intelligence represents our ability to creatively use existing knowledge, working memory, and other components of "thinking flexibly." Further, we tested if these patterns of association differed based on genetic risk. In this case, genetic risk was defined as having a family history of Alzheimer's disease or having 1-2 "bad" copies of the Apolipoprotein E (APOE) gene, which is the strongest genetic risk factor for Alzheimer's disease. (more…)
Author Interviews, Genetic Research, Hematology / 08.12.2020 Interview with: Steven Pipe, MD Professor of Pediatrics and Pathology Laurence A. Boxer Research Professor of Pediatrics and Communicable Diseases Pediatric Medical Director, Hemophilia and Coagulation Disorders Program Director, Special Coagulation Laboratory University of Michigan What is the background for this study? Response: Hemophilia B is an inherited bleeding disorder where patients are missing clotting factor IX (9), a critical blood clotting protein.  Patients with a severe deficiency are at risk for traumatic and spontaneous bleeds – primarily into joints.  Repeated bleeding into joints causes more than acute pain and swelling but also leads to inflammatory and degenerative changes in joints that eventually leads to severe debilitating arthritis that can be crippling.  To try to prevent this, patients as young as infants are placed on regular infusions of clotting factor IX concentrates.  The relatively short half-life of factor IX means patients must infuse on average once to twice a week.  These can only be delivered intravenously – parents and then patients themselves have to learn this.  Prophylaxis must be continued lifelong to try to prevent bleeding events and protect joint health over the lifespan.  This is a tremendous burden on the patient and their caregivers. Even with regular prophylaxis, joint bleeds may still occur and arthropathy may still ensue.  This is because the blood levels often reach critically low levels prior to the next infusion.  Gene therapy aims to deliver a functional copy of the factor IX gene such that the patient’s own liver will make a continuous supply of factor IX that is delivered to the bloodstream.  At steady state with levels close to or within the normal range, patients would no longer be subject to bleeding events and would not require prophylaxis any longer.  We hope that such a one-time treatment would produced durable, “functionally curative” levels of factor IX. (more…)
Author Interviews, Cancer Research, Genetic Research / 01.12.2020 Interview with: Nina Bhardwaj MD PhD Director of Immunotherapy Tisch Cancer Institute Icahn School of Medicine at Mt Sinai Ward-Coleman Chair in Cancer Research Professor of Hematology and Oncology What is the background for this study? Response: Neoantigens are novel antigens expressed by tumors as a result of somatic mutations or frame shift mutations. They can be very immunogenic and consequently they are being incorporated into cancer vaccine platforms. In most cases it is necessary to determine each patient’s individual mutations and customize their vaccine antigens accordingly. We sought to identify shared mutations in cancer antigens which are deficient in DNA repair mechanisms namely microsatellite unstable tumors. These tumors have mutations in genes that normally are responsible for ensuring that DNA is properly replicated. Because these genes encode proteins that ensure proper repair around micro-satellite areas (which contain short repeated sequences of DNA and are present in similar regions from one person’s genome to the next), when they are mutated, these regions may not be repaired. Consequently due to nucleotide deletions and insertions one gets frame shift mutations which result in new protein expression which can be shared across tumors, as has been observed for a few regions. We therefore did a comprehensive study of a subset of tumors to determine the breadth of shared frame shift mutations. (more…)
Author Interviews, Brigham & Women's - Harvard, Cancer Research, Genetic Research, Melanoma, Prostate Cancer / 23.11.2020 Interview with: Saud H AlDubayan, M.D. Instructor in Medicine, Harvard Medical School Attending Physician, Division of Genetics, Brigham and Women's Hospital Computational Biologist, Department of Medical Oncology, Dana-Farber Cancer Institute Associate Scientist, The Broad Institute of MIT and Harvard What is the background for this study? What are the main findings? Response: The overall goal of this study was to assess the performance of the standard method currently used to detect germline (inhered) genetic variants in cancer patients and whether we could use recent advances in machine learning techniques to further improve the detection rate of clinically relevant genetic alterations. To investigate this possibility, we performed a head to head comparison between the current gold-standard method for germline analysis that has been universally used in clinical and research laboratories and a new deep learning analysis approach using germline genetic data of thousands of patients with prostate cancer or melanoma. This analysis showed that across all different gene sets that were tested, the deep learning-based framework was able to identify additional cancer patients with clinically relevant germline variants that went undetected by the standard method. For example, several patients in our study also had germline variants that are associated with an increased risk of ovarian cancer, for which the surgical removal of the ovaries (at a certain age) is highly recommended. However, these genetic alterations were only identified by the proposed deep learning framework.     (more…)
Aging, Author Interviews, Genetic Research, McGill / 22.11.2020 Interview with: Richard C. Austin, PhD Professor and Career Investigator of the Heart and Stroke Foundation of Ontario Amgen Canada Research Chair in Nephrology McMaster University and St. Joseph’s Healthcare Hamilton, Ontario, Canada What is the background for this study? What are the main findings? Response: A previous study published in 2011 by my collaborator, Dr. Michel Chretien at the IRCM, identified a rare mutation in the PCSK9, termed Q152H. Individuals harboring this mutation demonstrated dramatic reductions in their LDL cholesterol levels and had a significantly lower risk of CVD. Furthermore, individuals harboring the Q152H mutation showed increases in longevity with no evidence of other diseases such as liver disease, cancer and chronic kidney disease. This Q152H mutation was unique with only 4 families in Quebec shown to harbor this genetic variant. In terms of its effect on PCSK9 expression/activity, the mutation at Q152H was precisely at the cleavage site in PCSK9 necessary for its activation. As a result, the Q152H mutation fails to be cleaved and activated, thereby blocking its secretion into the circulation. This is why the Q152H mutation is considered a loss-of-function PCSK9 mutant. Given our lab's interest in endoplasmic reticulum (ER) stress and ER storage diseases, we began to collaborate with Drs. Chretien and Seidah at the IRCM to investigate whether this Q152H mutant, when overexpressed in liver cells, would cause ER stress and liver cell injury. This was based on the findings that the Q152H mutant does not undergo autocatalytic cleavage and its subsequent secretion from liver cells. It is well known in the literature that the accumulation of misfolded or inactive proteins in the ER gives rise to ER stress and cell injury/dysfunction. As a result, we initially showed to our surprise that overexpression of the Q152H mutant in liver cells failed to cause ER stress BUT increased the protein levels of several important ER chaperones, GRP78 and GRP94, known to PROTECT against liver cell injury/dysfunction. As part of our JCI study, we furthered these studies to examine the effect of the Q152H mutant when overexpressed in the livers of mice. This is where we demonstrated that the Q152H mutation showed protection against ER stress-induced liver injury/dysfunction. (more…)
Author Interviews, Dermatology, Genetic Research / 20.11.2020 Interview with: Jillian F. Rork, MD Assistant Professor of Dermatology Dartmouth-Hitchcock Medical Center at Manchester and The Geisel School of Medicine Society for Pediatric Dermatology Member What is the background for this study? Would you briefly explain the genetic condition of Down syndrome? Response:  Down syndrome is the most common chromosomal abnormality, occurring in approximately 1 in 700 newborns in the United States.  Trisomy of chromosome 21 can result in multisystem involvement such as hearing loss, heart defects, autoimmune conditions and dementia. This study focuses on how trisomy 21 affects one of the body’s largest organs, the skin. Current literature addressing dermatologic conditions associated with Down syndrome is limited. There is often emphasis on rare skin conditions such as elastosis perforans serpiginosa, milia-like idiopathic calcinosis cutis, and eruptive syringomas. There is lack of consensus on incidence of more common disorders. We performed a retrospective chart review of 101 patients with Down syndrome in our dermatology practice at the University of Massachusetts to better describe associated skin conditions. (more…)
Author Interviews, Dermatology, Genetic Research, Melanoma / 19.11.2020 Interview with: Sarah I. Estrada, M.D., FCAP  Laboratory Director Affiliated Dermatology® What is the background for this study? What are the main findings? Response: As a dermatopathologist who makes diagnoses on lesions that may be melanoma, I’m faced with the reality that my accurate interpretation of biopsy tissue is key for the patient to be treated most effectively. Often histopathological evaluation is straightforward but not as often as I would like. The study presented here offers a new test that can be used in conjunction with my evaluation to determine if a questionable lesion is in fact melanoma. The test was developed to take into account the gene expression of the lesion which may factor in characteristics that I cannot visually observe. The test was validated and has shown very promising accuracy metrics. (more…)
Author Interviews, Genetic Research / 16.11.2020 Interview with: Philippe M Soriano, PhD Professor,  Cell, Developmental & Regenerative Biology and Oncological Sciences Icahn School of Medicine at Mount Sinai What is the background for this study? Response: The study was performed primarily to help understand how signals sent from growth factors to their receptors on the cell surface (see reply to the following question) initiate a cascade of events within the cells that lead to proliferation, survival, or other biological responses. This is important to know because deregulation of many of these pathways can lead to cancers. Would you explain what is meant by FGFs and their interaction with RTKs? Response: FGFs are cell signaling proteins that are also known as growth factors because they often lead to cell proliferation. They act by binding to receptors on the cell surface that are part of a family of receptor tyrosine kinases (RTKs). These RTKs are transmembrane proteins that have a domain outside of the cell that binds to the growth factor and a domain within the cell that has tyrosine kinase activity, hence the name “receptor tyrosine kinase (RTK).” This enzymatic activity adds a phosphate to a tyrosine residue of target proteins and starts a typical signal transduction pathway (referred to in the paper as “canonical”) leading to the usual biological responses (proliferation, survival, migration, etc.) (more…)
Author Interviews, Fertility, Genetic Research, OBGYNE, Technology / 29.10.2020 Interview with: PGT-A & ARTIFICIAL INTELLIGENCE IMPROVES PREGNANCY OUTCOMES FOR PATIENTS UNDERGOING IVF Interview with: Michael Large, PhD Senior Director, Research at CooperGenomics CooperSurgical What is the background for this study? What are the main findings? Dr. Large: Independent study results, presented at the recent the American Society of Reproductive Medicine (ASRM) Virtual Scientific Congress, demonstrated a 13 percent relative increase in ongoing pregnancy and live birth rates associated with the use of CooperSurgical’s PGTaiSM 2.0 technology to screen embryos for in vitro fertilization (IVF). The single-center study was conducted by NYU Langone Fertility Center (NYULFC), part of The Prelude Network. Preimplantation Genetic Testing for aneuploidy (PGT-A) is performed on embryos produced through IVF; it provides genetic information to help identify embryos that are more likely to result in a successful pregnancy. PGTai 2.0 technology is an advancement in PGT-A testing platform that utilizes artificial intelligence to increase objectivity of this screening process. The study compared results from three next generation sequencing (NGS) genetic tests: Standard NGS, NGS with first generation artificial intelligence (PGTai 1.0 Technology Platform) and NGS with second generation artificial intelligence (PGTai 2.0 Technology Platform). The ongoing pregnancy and live birth rates significantly increased by a relative 13 percent in the PGTai 2.0 group as compared to subjective and prior methodologies. Study results also suggest that the increase in ongoing pregnancy and live births may be linked to improvements in several preceding IVF outcomes (implantation rates, clinical pregnancy rates and pregnancy loss.) What should readers take away from your report? Dr. Large: This research moves us an important step closer to our goal of increased live births, improved pregnancy outcomes and further reduction of multiples in pregnancy through greater confidence in single embryo transfer. An estimated 48.5 million couples – approximately 15% of couples -- are affected by infertility worldwide. 80,000 babies were born with IVF in 2017 in the United States and more than one million babies were born in the period 1987 to 2015 in the United States as a result of IVF. What recommendations do you have for future research this study? Dr. Large: The goal of PGT-A is to decrease risk and maximize the chances of IFV success by screening for embryos with the highest potential. This was precisely what NYULFC have observed so far with PGTai 2.0 compared to older technologies. To fully appreciate the impact that these improvements are having for patients, we’re excited to hear from additional IVF centers across the world as they utilize this technology. Is there anything else you would like to add? Any disclosures? Dr. Large: The study demonstrates CooperSurgical’s commitment to developing the most advanced technology in the field of genetic testing to advance reproductive medicine and help families. By applying artificial intelligence in the PGTaism2.0 technology, we leverage mathematical algorithms derived from real-world data to achieve objective embryo assessment. I am the Senior Director of Genomics Research and Development at CooperSurgical. Michael Large, PhD, is the Senior Director, Genomics Research and Development at CooperSurgical. His team recently led and continues to develop state-of-the-art analytical methods for interrogating Reproductive Genetics. Dr. Large earned his PhD in Cell and Molecular Biology from the Baylor College of Medicine and his Bachelor of Science in Cell and Molecular Biology from the University of Wisconsin – La Crosse. Michael Large, PhD Senior Director, Research at CooperGenomics CooperSurgical What is the background for this study? What are the main findings? Dr. Large: Independent study results, presented at the recent the American Society of Reproductive Medicine (ASRM) Virtual Scientific Congress, demonstrated a 13 percent relative increase in ongoing pregnancy and live birth rates associated with the use of CooperSurgical’s PGTaiSM 2.0 technology to screen embryos for in vitro fertilization (IVF).[1] The single-center study was conducted by NYU Langone Fertility Center (NYULFC), part of The Prelude Network. Preimplantation Genetic Testing for aneuploidy (PGT-A) is performed on embryos produced through IVF; it provides genetic information to help identify embryos that are more likely to result in a successful pregnancy. PGTai 2.0 technology is an advancement in PGT-A testing platform that utilizes artificial intelligence to increase objectivity of this screening process. The study compared results from three next generation sequencing (NGS) genetic tests: Standard NGS, NGS with first generation artificial intelligence (PGTai 1.0 Technology Platform) and NGS with second generation artificial intelligence (PGTai 2.0 Technology Platform). The ongoing pregnancy and live birth rates significantly increased by a relative 13 percent in the PGTai 2.0 group as compared to subjective and prior methodologies. Study results also suggest that the increase in ongoing pregnancy and live births may be linked to improvements in several preceding IVF outcomes (implantation rates, clinical pregnancy rates and pregnancy loss.) (more…)
Author Interviews, Frailty, Genetic Research, Geriatrics, University of Pittsburgh / 13.10.2020 Interview with: Caterina Rosano, M.D., M.P.H. Professor of Epidemiology University of Pittsburgh Graduate School of Public Health What is the background for this study? What are the main findings? Response: Most people think about dopamine’s role in mobility in the context of Parkinson’s disease, but not in normal aging. We were curious to see if a genetic predisposition to produce more or less dopamine was related to mobility in individuals who had some level of frailty, yet did not have dementia, parkinsonism or any other neurological condition. While several genetic elements control dopamine signaling, my team and I focused on a gene called COMT, which breaks down dopamine to control its levels within the brain. We also considered the frailty status of participants, which is a common consequence of aging marked by a decline in physiological function, poor adjustment to stressors and a susceptibility toward adverse health outcomes. We suspected that frail participants could be particularly vulnerable to COMT-driven differences in dopamine levels. We examined this gene in more than 500 adults above the age of 65 in Pennsylvania, North Carolina, California and Maryland, excluding any participants taking dopamine-related medications or diagnosed with Parkinson’s disease. We then looked for potential links between genotype, frailty and speed. We discovered that frail participants with a high-dopamine COMT genotype had a 10% faster walking speed compared with participants with the low-dopamine COMT genotype.  (more…)
Author Interviews, Genetic Research / 30.09.2020 Interview with: Professor Sarah Medland Coordinator of the Mental Health Research Program and Group Leader Psychiatric Genetics QIMR Berghofer Medical Research Institute What is the background for this study? Response: This large collaborative project involving participants and researchers from around the world which has been underway for about 10 years. The aim was to try and identify genetic variants that influence handedness with the goal of increasing our knowledge about the way lateralization develops in behaviour and in the brain. In this project we were able to bring together results from cohort studies conducted by academic collaborators, the UK Biobank and 23andMe yielding a total sample size of over 1.7 million participants. Working with Professor David Evans the co-senior author of the paper (University of Queensland) and Dr Gabriel Cuellar-Partida the first author of the paper (formally UQ now at 23andMe) and the other researchers who worked on the project we meta-analysed the genome-wide association analysis results from the cohorts and were able to identify 41 genetic variants that influence left-handedness and 7 that influence ambidextrousness. (more…)
Author Interviews, COVID -19 Coronavirus, FASEB, Genetic Research / 25.09.2020 Interview with: David Gurwitz, PhD Associate Professor Department of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv Israel What is the background for this study? Response: We closely followed the news on COVID-19 epidemiology since it was declared a pandemic, and were puzzled by the low fatality rates reported in nearly all East Asian countries, even that clearly this was in part due to fast response; for example, Taiwan remains the best example for combatting the pandemic. My past research on serpins (serine protease inhibitors) made me wonder if ethnic differences in some of them are in part related to the relatively low COVID-19 morbidities and fatalities, as serine proteases, in particular TMPPRSS2, are strongly implicated in the SARS-CoV-2 respiratory track cell entry and infection. Additionally, serine proteases such as neutrophil elastase are highly implicated in inflammatory tissue damage. Guy Shapira, a graduate student of my colleague Professor Noam Shomron, examined mutation records in different ethnic groups for the entire human serpin gene family. He came up with the findings we report regarding a close correlation between national records of the frequencies of the two mutations PiZ and PiS, underlying alpha-1 antitrypsin deficiency, in 67 countries on the global scale, and the current COVID-19 fatalities in the same 67 countries.  (more…)
Allergies, Author Interviews, Genetic Research, Hepatitis - Liver Disease / 08.09.2020 Interview with: Takanori Takebe MD Director for Commercial Innovation, Center for Stem Cell and Organoid Research and Medicine (CuSTOM) Assistant Professor, University Cincinnati Department of Pediatrics, Cincinnati Children’s Professor, Institute of Research Tokyo Medical and Dental University, Japan What is the background for this study?  What are the main findings? Response: Drug induced liver injury (DILI) is rare yet highly unpredictable disorder that oftentimes causes drug failure withdrawn from the market during clinical trial even at a very rare incidence of DILI (1/10,000). Indeed, one particular drug TAK875 (Fasigliam) was the case despite promising efficacy. This not only disappoints patient but impact significant financial risk to pharmaceuticals. In collaboration with DILI genomics consortium at US, EU and UK, we’ve found +20,000 genetic make up (variants) defines potential risk of developing Drug induced liver injury thru amplifying cellular stress signal cascades that were investigated by human cell, organoid and patient datasets. (more…)
Author Interviews, Cost of Health Care, Genetic Research, Immunotherapy, Melanoma, Surgical Research / 03.09.2020 Interview with: Edmund K Bartlett, M.D. Department of Surgery/Division of Surgical Oncology Memorial Sloan Kettering Cancer Center New York, New York What is the background for this study? Response: Indications for adjuvant therapy for resected, high-risk melanoma is a controversial and rapidly-evolving topic in melanoma treatment. Immunotherapy treatments targeting PD-1 have significantly improved survival in advanced-stage disease, but the magnitude of survival benefit in stage III disease--particularly stage IIIA--remains unclear. Recently, 31-GEP (a gene expression profiling assay) has been studied as a risk-stratifying tool to identify patients who are at higher risk for systemic recurrence. Ideally such a tool could identify patients most likely to benefit from immunotherapy treatment in the adjuvant setting (when all visible disease has been removed). (more…)
Author Interviews, Genetic Research, Nature, NYU / 17.08.2020 Interview with: Professor Aneel K Aggarwal, PhD Pharmacological Sciences and Oncological Sciences Icahn School of Medicine at Mount Sinai What is the background for this study? Response: DNA polymerase ζ  (Pol ζ) is the crucial enzyme that allows cells to cope with DNA damage resulting from exposure to environmental and industrial carcinogens and to other daily genotoxic stresses. At the same time, Pol ζ has emerged as an important target for discovery of therapeutics in the treatment of chemotherapy-resistant cancers. What are the main findings?   Response: We have succeeded in resolving the 3-D atomic structure of the complete Pol ζ enzyme using cryo-electron microscopy. (more…)
Author Interviews, Genetic Research, Neurology / 11.08.2020 Interview with:
BrainHQHenry Mahncke, PhD
Chief Executive Officer BrainHQ
Dr. Mahncke earned his PhD at UCSF in the lab where lifelong brain plasticity was discovered. At the request of his academic mentor, he currently leads a global team of more than 400 brain scientists engaged in designing, testing, refining, and validating the computerized brain exercises found in the BrainHQ app from Posit Science, where he serves as CEO. Tell us what’s important about this new study in people with Down Syndrome? Response: Often, we believe that genetic conditions are predetermined and completely inalterable, but this new study underscores that, when it comes to the brain, positive change is almost always possible – regardless of age or health condition. That’s consistent with the science of brain plasticity, and it’s a very different and hopeful way to think about the potential of people with Down Syndrome – and people, generally. Can you briefly describe Down Syndrome and findings in this study? Response: Down Syndrome is one of the most common genetic abnormalities in humans, found in about 1 in 1,000 births each year, and caused by the presence of all or part of a third copy . of chromosome 21.It’s usually associated with physical growth delays and characteristic facial features. While cognitive abilities vary enormously, one study estimates the average IQ of a young adults is about 50 (comparable to average 8 or 9 year olds). In a pilot study among 12 people with Down Syndrome involving physical, cognitive and EEG measurements, researchers at Aristotle University of Thessaloniki, Greece, found a 10-week combined protocol of physical exercises and computerized brain training led to a reorganization of the brain and to improved performance on both cognitive and physical measures. The physical training consisted of aerobic, flexibility, strength, and balance exercises. The cognitive training used in the study was the Greek version of the commercially-available BrainHQ brain app, consisting of 29 visual and auditory exercises targeting memory, attention, processing speed, problem-solving, navigation, and social skills. The researchers had hypothesized that the training would trigger the brain’s neuroplasticity – its ability to change chemically, structurally and functionally. Their results showed increased connectivity within the left hemisphere and from left to right hemisphere, as well as improved performance on physical and cognitive assessments.   (more…)
Author Interviews, COVID -19 Coronavirus, Genetic Research, JAMA / 11.08.2020 Interview with: Caspar van der Made, MD Resident in Internal Medicine, PhD-student Alexander Hoischen, PhD Geneticist, Assistant professor, Departments of Human Genetics and Internal Medicine Radboud University Medical enter Nijmegen, The Netherlands  First author Caspar van der Made is a resident in Internal Medicine and PhD-student on the topic of immunogenomics. Alexander Hoischen is geneticist with a special focus on the application of genomic technologies in primary immunodeficiencies and last author of this study. What is the background for this study?   Response: This study was initiated to investigate the presence of monogenic factors that predispose young individuals to develop a severe form of COVID-19. It has become clear that several general risk factors such as obesity, hypertension and diabetes mellitus increase the risk of developing severe coronavirus disease. However, even though differences in interindividual genetic make-up are thought to influence the immune response to SARS-CoV-2, such specific genetic risk factors had not yet been identified. We therefore chose to study young brother pairs (sharing half of their genomes) without any general risk factors that nevertheless contracted severe COVID-19. We hypothesized these highly selected case series may offer the most optimal chance of identifying a (possible X-linked) primary immunodeficiency specific to COVID-19. (more…)
Author Interviews, Breast Cancer, Cancer Research, Genetic Research, Ovarian Cancer / 22.07.2020 Interview with: Prof Ranjit Manchanda MD, MRCOG, PhD Professor of Gynaecological Oncology & Consultant Gynaecological Oncologist NHS Innovation Accelerator (NIA) Fellow Integrated Academic Training Programme Director London Specialty School of Obstetrics & Gynaecology, Health Education England Specialty Research Lead for Gynaecological Cancer, NIHR, North Thames Clinical Research Network Cancer Research UK, Barts Centre | Queen Mary University of London Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine | Charterhouse Square | London Department of Gynaecological Oncology | Barts Health NHS Trust, Royal London Hospital What is the background for this study? Response: Around 10–20% of ovarian cancers and 6% breast cancers overall are caused by inheritable BRCA1/BRCA2 mutations. Women carrying BRCA1/BRCA2 mutations have a 17–44% risk of ovarian cancer and 69–72% risk of breast cancer until age 80 years. Most of these cancers can be prevented in unaffected BRCA1/BRCA2 women carriers. Women can opt for a range of options including screening, preventive, and reproductive choices to minimise their risk. The current approach uses established clinical-criteria/family-history (FH) based a priori BRCA probability thresholds to identify high-risk individuals eligible for BRCA testing. However, this requires individuals and health practitioners to recognise and act on a significant FH. BRCA carriers, who are unaware of their FH, unappreciative of its risk/significance, not proactive in seeking advice, or lack a strong FH (small families/paternal inheritance/chance) get excluded. Over 50% BRCA carriers do not fulfil clinical criteria and are missed. Despite >25 years of BRCA testing and effective mechanisms for prevention, current guidelines and access to testing pathways remain complex and associated with a massive under-utilisation of genetic testing. Only 20% of eligible women have accessed/undergone genetic testing and our earlier analysis showed that 97% of BRCA carriers in the population remain unidentified. Current detection rates are inadequate to identify all BRCA carriers and even doubling detection rates will not work. Why should we wait for decades for people to develop cancer before identifying BRCA carriers and unaffected at-risk family members to offer prevention?. This highlights substantial missed opportunities for early detection and prevention. A new population testing approach can change this. Jewish population studies show this is feasible, acceptable, has high satisfaction (91–95%), significantly reduces anxiety, doesn’t harm psychological well-being or quality of life, and is extremely cost-effective. However, this has not been evaluated in the general population and in particular across different  countries or health systems. The potential applicability and scope for this approach transcends continents and countries. Additionally, for interventions to be sustainable, they need to be cost-effective and affordable. We have undertaken a cost-effectiveness analysis of population based BRCA testing compared with current standard clinical testing of women designated as high risk, across high income countries (UK/USA/Netherlands), upper-middle income countries (China/Brazil), and low-middle income country (India). (more…)
Author Interviews, Genetic Research, Nature, Technology / 15.07.2020 Interview with: Dr.Altuna Akalin PhD Head of Bioinformatics and Omics Data Science Platform Berlin Institute for Medical Systems Biology (BIMSB) Max Delbrück Center for Molecular Medicine (MDC) Berlin, Germany What is the background for this study? Where does the word Janggu come from?  Response: Deep learning applications on genomic datasets used to be a cumbersome process where researchers spend a lot of time on preparing and formatting data before they even can run deep learning models. In addition, the evaluation of deep learning models and the choice of deep learning framework were also not straightforward. To streamline these processes, we developed JangguWith this framework, we are aiming to relieve some of that technical burden and make deep learning accessible to as many people as possible. Janggu is named after a traditional Korean drum shaped like an hourglass turned on its side. The two large sections of the hourglass represent the areas Janggu is focused: pre-processing of genomics data, results visualization and model evaluation. The narrow connector in the middle represents a placeholder for any type of deep learning model researchers wish to use.  (more…)
Aging, Author Interviews, Genetic Research / 24.06.2020 Interview with: Andrea Bodnar, Ph.D., Science Director Gloucester Marine Genomics Institute (GMGI) What is the background for this study? How does gene expression differ in the red sea urchin from humans?  Why is this animal not susceptible to age-related deterioration? Response: The red sea urchin is one of the earth’s longest-lived animals, living for more than 100 years without showing signs of aging. These animals grow and reproduce throughout their lives and show no increase in mortality rate or incidence of disease with age. This includes no reported cases of neoplastic disease, like cancer. To begin to understand the cellular mechanisms underpinning this extraordinary life history this study investigated gene expression patterns in the tissues of young and old red sea urchins. (more…)
Author Interviews, Dermatology, Genetic Research / 01.06.2020 Interview with: Sarah E. Millar, Ph.D. Director, Black Family Stem Cell Institute Professor, Departments of Cell, Developmental and Regenerative Biology and Dermatology Icahn School of Medicine at Mount Sinai New York, NY What is the background for this study? Response: One of the major roles of the skin is to serve as a protective barrier, both preventing external insults, such as toxins and pathogens, from entering the body, and helping to retain moisture. The mechanisms required for appropriate skin barrier formation remain incompletely understood. Elucidating these processes is important for understanding and developing improved treatments for dermatological diseases in which the skin barrier is dysfunctional, such as eczema and psoriasis. Understanding epigenetic regulators, proteins that modify the structure of genetic material, is an area of scientific interest, as many new drugs target these proteins. Importantly, multiple epigenetic regulators have been shown to be important in skin development. My lab has focused on one group of epigenetic regulators, histone deacetylases (HDACs), because HDAC inhibitors show promise for treating several different cancers and other disorders in which cell proliferation is poorly controlled. We previously showed that HDACs 1 and 2 are required for normal skin development. In the current study, we investigated whether the related protein HDAC3 is also important in establishing the skin barrier.  (more…)
Author Interviews, Diabetes, Genetic Research, Pancreatic / 15.05.2020 Interview with: Dr. Núria Malats, MD PhD, Head of the Genetic and Molecular Epidemiology Group Spanish National Cancer Research Centre (CNIO) What is the background for this study? Response: The high mortality of pancreatic cancer is a consequence of late diagnosis because of the absence of symptoms in the earliest stages, and defining risk populations is therefore crucial to be able to carry out diagnostic tests that reveal the presence of the tumour as early as possible. Diabetes and pancreatic cancer are connected because the pancreas secretes insulin; in diabetic people, this does not occur in a normal way. It is estimated that around 50% of patients with pancreatic cancer presents diabetes. But it is an outstanding challenge for researchers to figure out which is the cause and which is the consequence.  To conduct the study, the team used data from more than 3,500 persons from PanGenEU, a large European study involving centres from six countries, including Spain, and led by Malats, to analyse the relationship between multiple risk factors and pancreatic cancer. (more…)
Author Interviews, Cancer Research, Genetic Research, JAMA / 14.05.2020 Interview with:
  • Sung Jun Ma, MD, resident physician in Radiation Medicine at Roswell Park Comprehensive Cancer Center (first author)
  • Oluwadamilola T. Oladeru, MD, a resident physician at Massachusetts General Hospital Cancer Center What is the background for this study? Response: More than 40% of women with hormone receptor-positive, HER2-negative early-stage breast cancer have high recurrence scores (RS) of 26-30. Optimal adjuvant systemic therapy in this subgroup remains unclear, and national guidelines currently recommend either chemoendocrine therapy or endocrine therapy alone. In addition, the difference in overall survival of a patient with a RS 26-30 versus RS >30 is unclear. (more…)
Author Interviews, Brigham & Women's - Harvard, Gender Differences, Genetic Research, Nature / 13.05.2020 Interview with: Nolan Kamitaki PhD Harvard Medical School What is the background for this study? Response: Previous work from our lab found that the strongest common genetic association to schizophrenia is driven in part by copy number variation of the C4 genes.  Given that lupus and Sjogren's syndrome, two autoimmune disorders, have association patterns that span the same region of the human genome, we wondered if part of the signal for these diseases may also arise from variation of C4 given that both have hypocomplementemia as a characterizing trait.   The other main finding is that these associations appear to be sex-biased, where the protection from each additional copy of the C4 gene was greater in men than in women.  When we went back to the data used in the previous study from our lab association C4 variation to schizophrenia, we found that the effect was stronger in men there as well.  Although the expression of C4 at the RNA level does not appear to differ between men and women, we saw that men had more C4 protein in both cerebrospinal fluid and blood plasma, suggesting that this may explain the greater genetic association in men. (more…)
Author Interviews, Breast Cancer, Cancer Research, Genetic Research, JAMA / 08.05.2020 Interview with: Anurag K. Singh MD Professor of Oncology Director of Radiation Research Leader, Cell Stress and Biophysical Therapy Program Associate Dean Graduate Medical Education, Research Roswell Park Comprehensive Cancer Center Buffalo NY What is the background for this study? Response: More than 40% of women with hormone receptor-positive, HER2-negative early stage breast cancer with high recurrence scores (RS) have RS of 26-30. Optimal adjuvant systemic therapy in this subgroup remains unclear, and national guideline currently recommends either chemoendocrine therapy or endocrine therapy alone. In addition, the difference in overall survival of a patient with a RS 26-30 versus RS >30 is unclear.   (more…)