The Genetics Podcast

This week on The Genetics Podcast, Patrick is joined by Dr. Jagesh Shah, Chief Scientific Officer at Mirai Bio. They discuss why delivery is a central bottleneck holding back nucleic acid medicines, how Mirai's lipid nanoparticle (LNP) platform is built to reach tissues like adipocytes and T cells, and the machine learning feedback loop the company uses to engineer LNP formulations.
Show Notes
0:00 Intro to The Genetics Podcast
01:00 Welcome to Jagesh
01:40 Why delivery is the main bottleneck for gene therapies
03:42 Easier vs harder tissues to target for delivery
06:40 Overview of Mirai's modular delivery platform 
09:02 Comparing viral vectors and lipid nanoparticles (LNPs) 
12:18 Different approaches for targeting adipocytes and T cells with LNPs
15:49 Mirai's machine learning (ML) feedback loop for optimizing LNP formulation
20:50 Why lipid chemistry is still hard for ML to learn and factors affecting LNP tropism
24:35 Jagesh's path from academia to Mirai
27:23 Mirai's platform business model and how it lowers risk
29:13 What industry partnerships with Mirai look like
31:41 Mirai's next frontier of delivery to muscle tissue and the brain 
34:40 Cargo size and immunogenicity of LNPs vs AAV 
36:00 Why the field needs to close the regulatory pace gap 
37:19 Closing remarks
Find out more:
Mirai Bio

This week on The Genetics Podcast, Patrick is joined by Sharon Terry, President & CEO of Genetic Alliance. They discuss how Sharon established a layperson-led biobank, her long-term work on rare diseases and patient advocacy, and her program to bring genetic technology to patients in low- to middle-income countries. We’re re-running this episode for its enduring lessons on patient advocacy, rare disease parenting, communication, and citizen science. 

Show Notes
0:00 Intro to The Genetics Podcast
00:59 Welcome to Sharon and a discussion of the personal experience with rare disease that started her journey
03:47 Reasons Sharon decided to establish the first layperson-led biobank
05:34 Challenges with setting up the biobank infrastructure
07:00 Balancing financial factors in a non-profit organization 
09:30 Recent patterns and future insight into rare disease drug discovery framework and regulation
15:32 Barriers to widespread collaboration and cooperation in rare disease research, and why it should be approached from a public health perspective
18:12 Background and experiences from the iHope Genetic Health program in low- to middle-income countries
24:44 Sharon’s perspective on challenges with the Genetic Information Non-discrimination Act
28:49 Sharon’s lessons learned in her patient advocacy and policy work, and her hopes for future legislation
33:04 Sharon’s hopes for improved access to genetic testing and treatment for children in underserved communities
34:34 How Sharon learned about rare diseases and genetics as a “homeschooling mom without a degree”
37:54 Insights into how elements of spirituality can support advocacy work
40:18 Closing remarks

This week on The Genetics Podcast, Patrick is joined by Dr. Carl Anderson, Senior Group Leader and Head of the Human Genetics Programme at the Wellcome Sanger Institute, where he leads the Genomics of Inflammation and Immunity Group. They discuss IBDVerse, the single-cell atlas Carl's team built to map genetic effects on gene regulation across gut cell types, how coding and non-coding variants converge on shared biological pathways in inflammatory bowel disease, and Carl's vision for longitudinal multi-omics cohorts built around the sickest and most underrepresented hospital patients.
Show Notes
0:00 Intro to The Genetics Podcast
00:58 Welcome to Carl
02:05 The origins of IBDVerse and mapping genetic effects on gene regulation across gut cell types in IBD
05:43 How anti-TNFs and newer genetically-supported IBD drugs have reshaped treatment 
08:04 Genetic versus environmental contributions to IBD
09:53 Using single-cell data to uncover IBD disease subtypes
13:22 Drug sequencing and immunogenicity in treatment response
16:52 The backstory of building the IBDVerse atlas at scale
20:29 How coding and non-coding IBD variants converge on the same genes and pathways
23:38 The case for pathway-specific polygenic risk scores
28:17 Building a longitudinal multi-omics dataset to predict IBD progression and drug response
30:08 Why Sanger's next cohort targets sick and underrepresented patients rather than healthy volunteers
34:07 What Carl looks for when interviewing PhD students and faculty candidates 
39:20 A call to junior scientists and closing remarks
Find out more:
IBDverse study

This week on The Genetics Podcast, Patrick is joined by Dr. Pradeep Natarajan, Director of Preventive Cardiology at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School. They discuss the discovery of clonal hematopoiesis as a driver of cardiovascular disease, the inflammatory mechanisms and emerging therapies targeting it, the growing clinical case for polygenic risk scores, and Pradeep's upcoming move to lead cardiometabolic and human genetics research at Amgen.
Show Notes
0:00 Intro to The Genetics Podcast
00:59 Welcome to Pradeep
01:30 The origin story of clonal hematopoiesis (CH) as a cardiovascular risk factor 
09:41 CH mutations such as TET2 that are linked to cardiovascular disease
12:27 Evidence tying inflammation to CH and drugs that could target it
16:49 TenSixteen Bio’s strategy for targeting CH and the challenge of finding the right patients
21:33 Trajectory of CH across age and somatic mosaicism beyond blood
26:44 How polygenic risk scores fill a gap in cardiovascular risk prediction
34:49 The future clinical applications of polygenic risk scores
39:20 The challenge of standardizing polygenic risk scores for clinical and regulatory use
42:27 Pradeep's move to pharmaceutical company Amgen and his reasons for it
46:23 Closing remarks
Find out more:
Clonal hematopoiesis paper

This week on The Genetics Podcast, Patrick is joined by Dr. Christopher Walsh, Professor of Pediatrics and Neurology at Harvard Medical School, Chief of Genetics and Genomics at Boston Children's Hospital, and HHMI Investigator. They discuss his path from neurobiology to human genetics, how somatic mosaicism in the brain drives disease from epilepsy to Alzheimer's, and what this reveals about new therapeutic targets for neurodegeneration.
Show Notes
0:00 Intro to The Genetics Podcast
00:59 Welcome to Chris
01:18 Chris’ path from neurobiology to human genetics
04:55 How collaboration and mentorship have shaped Chris' career
06:59 Somatic mosaicism and genetic mutations in the brain, from epilepsy to Alzheimer’s
13:56 Repurposing cancer therapeutics and targeting DNA damage as new approaches to Alzheimer's
15:29 A shared pattern of DNA damage across neurodegenerative diseases and the mechanism behind it
19:36 How healthy neurons accumulate mutations with age and what that means for the brain
23:21 How mutation rates and patterns vary across cell types
26:23 How genome quality control and synaptic pruning may explain both brain development and neurodegeneration
30:33 Why some people maintain a healthy brain into old age
33:57 Chris’ advice for early-career scientists on pursuing goals
36:43 Closing remarks
Find out more:
https://walshlab.org/