The Genetics Podcast

Join Patrick Short and Professor Clare Turnbull, Professor in Translational Cancer Genetics at the Institute of Cancer Research, as they discuss polygenic risk scores and their application in healthcare. Delve into the complexities of predicting disease, the challenges of screening programs, and the potential impact of integrating genomics into healthcare systems. Discover the limitations and potential of polygenic risk scores and gain valuable insights into the future of personalized medicine. 0:00 Intro 1:00 Clare’s path to becoming a clinical geneticist and her research in uncovering genetic links to cancer 3:20 How do Polygenic Risk Scores help to predict disease, particularly breast cancer? 10:00 The influence of environmental and genetic effects on breast cancer presentation 11:30 Next clinical steps after determining genetic risk for breast cancer 17:30 How effective and accurate are polygenic risk scores in predicting various types of cancer, given the potential for false positives or negatives? 25:00 The potential for integrating genetic screenings and polygenic risk scores into early cancer diagnosis 27:20 How do monogenic risk scores like BRCA 1 and 2 fit into the paradigm of cancer research? 31:30 Using both monogenic and polygenic to explain population prevalence of disease 35:00 Integration of genomics and genetic screenings into the UK healthcare system 40:30 What comes after the genetic test? What is the use in identifying risk for a disease if nothing is subsequently done to prevent it? 44:50 Clare’s upcoming work in remodeling NHS systems for evidence protocols and clinical use of genetic tests 46:50 Closing remarks

In this episode, Patrick is joined by Dr. Mike Severino, CEO of Tessera Therapeutics and CEO-Partner of Flagship Pioneering. Join us as Mike walks us through Tessera’s approach to treating genetic diseases by rewriting bases, exons, or even whole genes with a novel approach called Gene Writing. 0:00 Intro 1:00 What prompted you to join Flagship Pioneering? 3:32 How is Flagship able to innovate and invent novel therapies in ways that Big Pharma companies may find difficult? 5:00 Introduction to gene writing and the role of Tessera Therapeutics 8:22 The current limitations and challenges of gene writing 10:22 Gene knockouts vs gene writing – which is more useful for genetic therapies? 12:30 Reasons why the liver the most commonly targeted organ for gene therapies 19:00 Lipid Nanoparticles and their role in gene writing 22:45 How do you guide mobile genetic elements to write genes in the intended location? 25:20 Development of gene writing technology since 2018 28:15 The implications of gene writing for diseases like PKU, Alpha-1 antitrypsin deficiency, sickle cell disease, and cancer 34:00 Next steps on the way to clinical trials 36:46 Using genomics and computational biology to guide measurable outcomes in drug discovery and development 40:15 Using gene writing to address rare developmental diseases 43:32 Closing remarks

0:00 Intro 0:45 The founding of BioTx.ai 4:35 How do algorithms for ‘causal inference’ work? 6:30 Modeling gene interactions for genetic disorders 8:35 How to predict gene interactions 10:30 What happens after identifying a potential gene variant or interaction? 14:35 How can you use machine learning to determine causal relationships between gene variants and disease? 17:30 Deconvoluting genes and traits, and their impacts on effect size 19:20 Key ingredients in determining causal relationships: data and computational power 21:10 Limitations of using machine learning to find genetic determinants of rare diseases 24:30 Predicting clinical outcomes with Biotx.ai 28:05 Machine learning enhances efficiency in the pre-clinical phase 29:40 Population genomics in Germany 32:50 Marco’s career decisions – starting a company vs. continuing in academia 35:50 The pros and cons of industry 38:10 The gaps in industry and academia 41:20 Closing remarks

Join Patrick in welcoming Dr. Bettina Lundgren, CEO of the Danish National Genome Center. Bettina is spearheading the development of personalised medicine in Denmark with a focus on integrating genome sequencing directly into the healthcare system. She is dedicated to fostering international collaboration in research and healthcare delivery. Tune in to learn about the one of the leading national scale genomics initiatives, and Bettina’s r insights on the future of personalised medicine! 0:00 Intro 0:56 Bettina’s path to genomics 1:47 Aspirations of the Danish National Genome Center 4:18 Comparing the Danish National Genome Center to other global genomics programs 8:10 Goal to sequence 60,000 whole genomes by 2024 11:40 The biggest challenges of integrating genomics with healthcare 15:30 Navigating the politics of privacy and data sharing 20:02 Complexities of sharing data across diverse regions and healthcare systems 23:28 Partnerships across borders: Sweden, Europe, and the world 28:10 Looking forward 10 years: strategies and novel developments in personalised healthcare 31:25 Final Thoughts 32:37 Outro

In this milestone episode, we welcome Dr Matthew Hurles, geneticist and pioneer in the field of human genomics. Dr Hurles has dedicated his career to unravelling the secrets hidden within our DNA, as well as harnessing cutting-edge research to revolutionise our understanding of genetic disorders, human evolution, and the potential for personalised healthcare. Join Patrick and Matt as they delve into the frontiers of genomic science, from the implications of newborn screenings to emerging technologies and the transforming role of researchers. 0:00 Intro 1:55 Genetics in the ’90s compared to genetics today 4:30 Work-life balance in science 8:00 Deciphering Developmental Disorders (DDD) study 13:10 New technologies in genome sequencing 14:45 How far are we from using next-generation sequencing as standard for diagnosing rare disease? 17:10 The Industrialization of genomics research 21:10 Will we move to a world where everyone is sequenced at birth? 25:20 Uses for cellular assays in healthcare and research 27:15 Bridging the gap between rare and common diseases 31:35 Birth cohorts and newborn screening studies 33:30 The power of early diagnosis and intervention with genomics 36:30 Open access databases 38:40 Advice for early-career researchers 41:20 Future directions for the Wellcome Sanger Institute 43:30 Applications of artificial intelligence and machine learning in genomics 45:30 Thank you 46:50 Outro

Join us for EP99 of The Genetics Podcast as Patrick dives into the extraordinary career and work of Dr. Harold E Varmus, a Nobel laureate scientist, former director of the National Institutes of Health, president of Memorial Sloan Kettering Cancer Centre, and director of the National Cancer Institute. Join Patrick and Harold as they navigate the complex landscape of cancer, from advancements that have revolutionized the field to diversity in cancer research and the Polyethnic-1000 Genome Project. This compelling episode is punctuated by Harold’s personal reflections, and invaluable learnings from his career. 1:27 Why a Beowulf quote made its way into Harold’s Nobel Prize acceptance speech 2:28 How it feels to hear you have won a Nobel Prize 4:04 How did fulfilling a national responsibility during the Vietnam War lead to a Nobel Prize 7:54 Areas of cancer research that are moving forward, and areas that are more stubborn 9:44 The formidable hurdle of metastasis 11:00 The educational power of COVID 12:33 Cancer and evolution: why is cancer so difficult? 14:50 Introducing the Polyethnic-1000 Genome Project 19:35 Working with WHO to ensure genomic technologies are accessible to all 23:03 What are the biggest blockers to the widespread adoption of genomics? 26:00 Context switching: From ‘deep’ science to stepping into the role of director 28:50 Learnings on how science is funded and coordinated 33:05 Discussing the allocation of funding: small grants Vs. large, coordinated efforts 36:16 Co-founding PLoS and PubMed Central 39:49 Accelerating the shift towards more open science 44:44 Just how close are we to curing cancer? 48:00 Studying cancer rates in mammalian species

In this episode, Patrick is joined by Alex Cagan, a Postdoctoral Fellow in the Cancer, Ageing and Somatic Mutation programme at the Wellcome Sanger Institute, specialising in evolutionary processes in somatic tissue. Tune in as Alex walks us through a fascinating new study, years in the making, looking at somatic mutation rates across 16 mammalian species, spanning 30-fold in lifespan and around 40,000-fold in body mass. This work sheds light on fundamental questions in cancer and ageing across the tree of life. 0:00 Intro 6:00 Collaborating with the London Zoo, and the challenges of sourcing tissue from long-living animals 9:06 Why are naked mole rats so important to the cancer and ageing community? 11:32 The scale and breadth of species sampled in the study 14:53 Is there a ceiling to how many mutations an organism can tolerate? 17:53 Why are intestinal crypts so effective for sequencing somatic mutations? 20:44 Key learnings from driving a 5-year study into somatic evolution 22:46 Are there really any “immortal” species, and what are they? 25:19 Why are cancer rates lower in larger species, and is this related to lower mutation rates, DNA error correction or both? 27:24 Investigating transmissible cancers in Chernobyl 29:40 Is cancer everywhere in the tree of life? 31:23 Alex talks about applying his talent for illustration to science 38:56 The Sanger Tree of Life program, the Darwin Tree of Life project, and the bright future ahead for research on somatic mutations 40:14 Outro Find out more about the study: https://www.nature.com/articles/s41586-022-04618-z

In this episode, Patrick is joined by Cindy Lawley, Senior Director of Population Health at Olink Proteomics and co-host of the Proteomics in Proximity podcast. Cindy has worked with major population genomics programs, including the UK Biobank, to bring together proteomics, genomics, and deep phenotyping using the Olink platform. Olink is one of the most promising proteomics technologies on the market, and the platform has been used in >1,000 publications, including landmark work in the UKBiobank to integrate genomics and proteomics. The largest Olink assay currently covers around 3,000 proteins, and the scale continues to grow, while costs are decreasing, paving the way for larger integrated proteomic and genomic data sets in the future. Join Cindy and Patrick for this 45-minute episode as they explore: how population-scale proteomics is driving novel discoveries different proteomics technologies, cost and throughput trajectories, and what is on the horizon surprising findings from longitudinal sampling of proteins And much more. If you would like to hear more from Cindy, listen to the Proteomics in Proximity podcast when you follow the link below. https://podfollow.com/1645900688

Food is medicine. And leveraging its power to heal isn’t a new concept. In fact, roughly 50% of all small-molecule medicines are derived from nature. But what if we could use AI to better understand the biology of the millions of molecules humans already consume? What if we could then apply this information to identify new treatments for chronic diseases? This week, we’re welcoming the CEO of Montai Health, Margo Georgiadis, to the podcast to discuss their AI platform that uses literature and wet lab experiments to analyse “the most privileged chemistry on Earth” to find new treatments for chronic diseases. Join Patrick and Margo for this hour-long episode, as they explore how Montai is leveraging technology to develop medicines based on the chemistry of food. From why ‘Anthromeolecules’ represent an abundant source of opportunities for drug discovery to the potential for AI to accelerate drug discovery and healthcare, this jam-packed episode celebrates the intersection of nature and technology. After listening to this hour-long episode, you will: understand Anthromolecules, and how the millions of molecules we already consume could be developed into new medicines know how AI can be leveraged to build a ‘ChatGPT’ to learn the language of biology and chemistry recognise Margo’s journey into biotech and healthcare, from her roots in the tech industry

Progress in AI is accelerating, and the potential in healthcare and precision medicine is enormous. In 2019, we had the pleasure of speaking with Dr Eric Topol, author of ‘The Patient Will See You Now’ and ‘Deep Medicine’. Eric has had an incredible career which has been largely focused on researching cardiovascular disease and heart attacks, both of which he worked on in the Cleveland Clinic and Scripps Institute.  Now, we’re reposting the interview as the conversation is more relevant than ever. Join Patrick and Eric as they discuss wireless medicine and the role of artificial intelligence and machine learning in medicine and healthcare.