The Genetics Podcast

Latest Episodes:

EP 121: Breakthroughs and insights in ALS research with Dr. Michael Benatar Feb 08, 2024

Show notes

Summary:
0:00 Introduction
0:50 Reflections from the 34th International Symposium on ALS/MND in Basel
1:50 Michael’s professional journey, initial challenges he encountered, and how the field of neurology has evolved over the years
3:10 An introduction to the ALS landscape, including its presentation, the genes involved, and potential treatment options
4:50 A framework for the stages of ALS, from being at risk to phenotypic conversion, and ultimately to the manifestation of disease symptoms.
8:00 The ALS-FTD axis and a broader perspective on the spectrum of neurodegenerative diseases
10:50 Potential genetic modifiers of ALS, including C9orf72 and SOD1, and future research
11:55 A refined approach to identifying precise biomarkers for ALS
15:15 The potential of phenotypic reversal in adult ALS patients undergoing ASO therapy
17:50 An introduction to the global ATLAS trial and applying therapies to pre-symptomatic populations
21:30 The broadening the ATLAS trial to include other genetic forms of ALS
23:20 The identification of additional biomarkers for ALS that may allow for earlier diagnosis or provide more insights into ALS
25:50 Holistic care for the ALS community, including patients and their loved ones
30:40 The evolving picture of genetics and ALS, beyond known monogenic risk factors
36:00 Michael’s 2016 publication in Neurology: Presymptomatic ALS genetic counseling and testing: Experience and recommendations
37:45 The need for legal protection from insurance policy changes given predictive biomarker results
38:30 Looking ahead 10-20 years: What will prove transformative in the next decade for ALS research and treatment?
41:30 Exploration of a generalized treatment for neurodegenerative diseases and the potential to leverage a universally-protective genetic mechanism
42:10 Closing remarks and gratitude for the those working to improve the lives of ALS community

EP 120: Exploring the frontiers of gene therapy and AAVs with Dr. Nicole Paulk, CEO and Founder of Siren Biotechnology Feb 01, 2024

Show notes

0:00 Introduction to Dr. Nicole Paulk, a pioneer in AAV research and the founder of Siren Biotechnology
0:50 The moments that shaped Nicole’s career path and her passion for gene therapy and AAV research
9:20 Nicole’s academic research career and her transition from academia to the biotech industry
23:00 The story behind the founding of Siren Biotechnology
30:11 Major challenges and breakthroughs in developing Universal AAV Immuno-Gene Therapy and vectorising cytokines.
36:00 Long-term impacts of using gene editing to target oncogenes
37:30 Challenges of 2023 in the startup field and Nicole’s expectations for 2024
42:00 Academia vs. Industry: Research processes and the pace of grant writing and innovation
46:40 Closing remarks

EP 119: Revolutionising drug discovery: how the Pharma Proteomics Project is combining genetic and proteomic data with Chris Whelan Jan 25, 2024

Show notes

0:00 Introduction
01:00 Chris’ background and career to date
02:10 What is the Enigma Project?
04:48 How is genetics being applied to drug discovery today and how does proteomics fit in?
09:23 When the UKBiobank Pharma Proteomics Project began and how long it took to set up
10:57 54k UK Biobank participants tested - discussion of findings
14:33 The project has carried out GWAS on nearly 3k proteins
15:18 Are there plans to scale the project and what do the team hope to discover through larger scale work?
18:10 Which areas of biology has the project provided a good insight into and which have proved more challenging
19:30 Are there projects of a similar scale where it would be possible to focus more on neuroscience?
21:31 Is reaching numbers akin to 100 million whole genomes required to fully leverage genetic data in drug discovery?
25:00 Causal or correlated? Medelian randomisation as an important tool for drawing the link from gene to protein and identifying relevant phenotypes
27:12 The causal proteins for the majority of neurological diseases are not differentially or cross sectionally changed
28:50 The future prospects of serial sampling and what is the potential value vs logistical burden
31:05 Imaging derived phenotypes: Integration of brain scan data with genetics
32:32 How well can brain organoids or other kinds of cellular systems match what’s going on in the actual brain?
35:30 The most exciting developments in the field we might see in the next couple of years
37:45 Closing remarks
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EP 118: The role of genetics in drug discovery and development with Dr. Matt Nelson Jan 18, 2024

Show notes

Summary:
0:00 Introduction
5:45 Lessons learned from 15 years at GSK: How has genetics and drug discovery evolved over time?
8:10 Matt’s seminal 2015 paper: Quantifying the impact of human genetic evidence on the probability of success in drug development
11:40 Which types of genetic evidence are the best drivers of success in clinical trials?
13:30 Matt’s 2023 paper ‘Refining the Impact of Genetic Evidence on Clinical Success’
18:15 Comparing the value of scale in patient-reported data and genotype arrays (e.g. 23andMe) to deep clinical phenotypes and exomes (e.g. UKBiobank)
23:00 The next leaps forward in newborn and population screening
23:50 Targeting genetic subtypes in drug development
26:15 The role of polygenic risk scores in drug development and the early proof of concept studies
28:15 Proactive trial design to exclude participants who might experience safety risks
30:20 Gene editing technologies for rare Mendelian diseases and Verve Therapeutics approach to treating familial hypercholesterolemia
33:40 Looking forward: The role of drug development in preventing disease
35:50 Matt’s transition from GSK to Deerfield and GenScience
38:00 How the role of genetics and genomics in healthcare investment has changed over the past 10 years
39:00 Genscience’s vision to use genomic data for drug discovery and decision-making
43:25 Looking forward: Linking genetic data to electronic health records in the US and Europe
47:50 Closing Remarks

EP 117: Wendy Chung: whole genome newborn screening and other big opportunities in genomic medicine. Jan 11, 2024

Show notes

Summary:
0:00 Introduction
1:45 Wendy’s early career looking into the genetics of diabetes through mouse models
6:23 A high altitude view: Cutting through hype to spot the next wave of game-changing technology
8:03 The role of policy and communication: how Wendy’s work goes beyond the lab to create real-world impact
11:20 Wendy’s choice to do an MD PhD, and how that impacted her research career
13:50 What we knew about autism and neurodevelopment in the 2010s, and what we know now
18:05 The biggest opportunities for the treatment of rare and ultra-rare diseases
25:00 Breakthrough advances in newborn genetic screening, lessons learned from success in Spinal Muscular Atrophy (SMA)
31:29 The GUARDIAN Study: reporting on whole genome sequencing for 250 conditions and the question of cost-effective screening
37:34 Surprising revisions of our understanding of variant pathogenicity and penetrance
40:22 GUARDIAN study: Eight thousand babies from New York City successfully screened
41:33 The percentage of actionable cases arising from broad newborn whole genome screening
43:50 How do we get to universal whole genome sequencing that the healthcare system can responsibly pay for?
47:11 Closing remarks

EP 116: Genetics and Medicine: Clonal hematopoiesis, genomics in healthcare, and a new discovery in APOL1 kidney disease with Dr. Alex Bick Jan 04, 2024

Show notes

0:00 Introduction
4:23 Insights into clonal hematopoiesis from the pioneering Framingham Heart Study
8:30 Linking clonal hematopoiesis to cancer and cardiovascular health
11:22 Interplay of germline and somatic variants in clonal expansion
17:20 How the rate of clonal expansion can provide insights into cancer and cardiovascular risk
19:00 How clonal hematopoiesis interplays with other orthogonal risk factors, including polygenic risk scores, and more established conventional heart health measures
21:00 Integration of genomic data in medical care, leading to the rise of preventative medicine
25:50 Insights into the Vanderbilt Genomics and Therapeutics Clinic
30:00 A dive into the Million Veterans Program, including the discovery of a modifier variant in the APOL1 gene related to kidney disease
44:05 How to differentiate the effects of modifier variants from risk variants in genetic studies
51:00 Individuals with APOL1 loss of function and its implications in kidney health
55:45 Closing remarks

EP 115: The Biggest Stories of 2023 with Dr. Veera Rajagopal (Part 2) Dec 27, 2023

Show notes

In the second instalment of our annual round-up episode, we welcome back Dr. Veera Rajagopal to cover the biggest stories in genetics and precision medicine of the last 12 months.
Don’t forget to give the first instalment of our 2023 round-up a listen.
Veera is a scientist at Regeneron with an interest in human genetics and drug target discovery in neuroscience and psychiatry. He is a prolific writer as well, both on his substack, GWAS Stories, and on Twitter, @doctorveera. Join us as Patrick and Veera cover the highlights of 2023, from milestone discoveries in South Asian genetics to cracking a 25-year-old genetic puzzle.
Summary:
00:00 Introduction and Part 1 recap
01:04 Understanding South Asian genetics

21:31 Low-hanging fruit

The ‘low-hanging fruit’ discovered earlier in the GWAS timeline, requiring just a few hundred participants.
An early-breaking story in Nature explores the underlying link between GDF15 (a hormone that is elevated during pregnancy) and a pregnancy-associated medical condition characterised by severe nausea.
Genome-Wide Association Studies (GWAS) of Reynaud’s phenomenon have been reported by two independent teams, who uncovered a strong signal near ADRA2A.

45:16 Rare variant discoveries

Momentum continues for rare variant discoveries based on UK biobank exome sequencing.
Gene BSN (Bassoon) continues to fascinate in 2023, as it’s discovered that it likely plays a key role in neurodegeneration.
In the world of non-coding variants, FOXA2 non-coding deletions are found to cause congenital hyperinsulinism and the loss of ZNF808 results in aberrant activation of silent transposons.

1:03:38 Tandem repeats

Paper from Decode quantifies the impressive mutation rate of STRs, which will put the de novo mutation rate of other variants to shame.
Paper from Po Ru Loh’s group shows that for two of the GWAS loci discovered early in the timeline, the causal variant is likely VNTRs.
A story from ASHG on Huntington highlights a major advancement in the understanding of HTT repeat-mediated neurodegeneration.

1:23:18 Looking to the future

The new and old genetic discoveries being translated into medicines.
A 25-year-old genetic puzzle that’s been solved using long-read sequencing.
Innovations in phenotyping and quantifying cellular phenotypes using microscopy.
Using discarded embryos to run genetic associations.

1:32:27 Concluding remarks

EP 114: The Biggest Stories of 2023 with Dr. Veera Rajagopal (Part 1) Dec 21, 2023

Show notes

0:00 Introduction

1:30 Veera’s personal highlights of 2023

Publication in Nature Genetics: Rare coding variants in CHRNB2 reduce the likelihood of smoking, an exome-wide association study identifying rare coding variants in CHRNB2 that may reduce the likelihood of smoking.
Designing cover art
Genetic links to neural circuits and their role in addiction

10:50 The most exciting story of the year: the first successful translation of a GWAS discovery into medicine

A milestone year in GWAS-driven drug development: FDA Approval of Casgevy, a cell based gene therapy for the BCL11A transcription factor, in the US and UK to treat sickle cell disease
Strong genetic support for the ongoing development of APOL1 inhibitors to treat kidney disease
Additional disease modifier variants, including the APOE4 variant in Alzhemer’s Disease

34:52 How rare Mendelian diseases can offer insights into drug developments

Looping back to BCL11A: how neurodevelopmental disorder patients with BCL11A haploinsufficiency provided insights into sickle cell treatment
BCL11A knockdown to induce fetal hemoglobin production and alleviate sickle cell disease
Recessive mutations in HMGCR provide the missing link into why statins can induce myopathy. Learn more in this Atlantic article.
The often underappreciated importance of studying rare Mendelian diseases

51:31 The value of common variants vs rare variants in informing drug targets

Why are pharmaceutical companies studying rare variants?
How the FTO locus associated with obesity highlights challenges in identifying causal gene variants
Surprising twists in translating mice physiology to human physiology, and decades-long quest to understanding the mechanism behind this extremely early GWAS hit

1:00:32 Genetic drift, endogamy, and consanguinity

The rise of large-scale studies looking beyond European populations
The FinnGen study: a significant step forward in understanding the genetic basis of diseases in founder populations
Interesting discoveries from integrating non-European populations in biobanks and Direct to Consumer databases
A recent 23andMe paper that identifies a founder variant in Puerto Rican populations associated with a strong risk effect on cataract development

1:13:40 Concluding remarks and looking ahead to Part 2!

Check out Veera's substack, GWAS Stories, and follow him on Twitter, @doctorveera

EP 113: Harnessing human genetics to discover co-evolved small molecule medicines with Dr. Jason Park, CEO of Empress Therapeutics Dec 07, 2023

Show notes

In this episode of The Genetics Podcast, we welcome Dr. Jason, founder and CEO of Empress Therapeutics, a Flagship Pioneering company. Join us as we discuss how human genetics can identify small molecules with therapeutic potential that are already created by our bodies, paving the way for faster discovery of new medicines.
Summary:
0:00 Intro
1:20 Understanding parts of the genome that create and modify small molecules
5:50 The central dogma of molecular biology
8:50 Jason’s background founding biotech companies
11:45 Flagship pioneering: combining scientific discovery and engineering innovations
13:10 The foundation of Empress Therapeutics: biological insight, data, and artificial intelligence
19:30 Learning from disease states and following the thread from DNA to small molecule
22:20 Differences in genetic chemistry across people and case studies
25:30 Potential biological limitations of the small molecule approach
28:00 Using human genetics and synthetic biology to create impactful medicines
32:00 What happens in ‘stealth mode’
36:00 The limiting reactant of scaling small molecule therapies to a wider platform
38:20 The role of the metagenome
40:00 Lessons learned from founding multiple companies
42:20 Origins of the name Empress Therapeutics
43:40 Closing remarks

EP 112: Making the leap: the scientists collaborating to transform genetic targets into next generation treatments, with David Ochoa Nov 23, 2023

Show notes

This week on The Genetics Podcast Patrick is joined by David Ochoa, Platform Coordinator at Open Targets. They discuss how the Open Targets platform is enabling game-changing collaboration between academic research and big pharma. Working with partners including Sanofi, GlaxoSmithKline, Bristol Myers Squibb, Genentech and Pfizer, Open Targets powers collaboration between some of the world’s biggest drug development pioneers and most renowned academic institutions with the goal of accelerating production of effective drug treatments.
But while the pre competitive approach enables huge time and money savings for all stakeholders, it relies on effective coordination and alignment - David explains how Open Targets tackles the inherent challenges to allow this world-leading consortium to build the future of next generation treatments.

00:03 Introduction
04:33 Thetypes of data sets used for target discovery
08:08 Managing the heterogeneity of data sets
13:29 David Ochoa's career trajectory, and entry into Open Targets
18:28 Addressability of diseases and targets by different modalities
22:24 Retrospective analysis of genetic evidence in drug approvals
36:58 Future focus on revamping Open Targets genetics
39:54 Exploring somatic variation and mutational scanning
42:49 Clinical trial stoppage
48:22 Closing remarks

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