The Genetics Podcast

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/

This week on The Genetics Podcast, Patrick is joined by Yentli Soto Albrecht, physician-scientist in training and founder of CureC9. They discuss how losing her father to C9orf72 ALS, and later learning her own genetic risk, reshaped the direction of her career. The conversation explores the biology linking the C9 repeat expansion to ALS and FTD, and how CureC9 is removing barriers across biomarkers, therapeutics, and patient samples to accelerate progress toward a cure.
Show Notes
0:00 Intro to The Genetics Podcast
00:58 Welcome to Yentli
02:34 How Yentli's father's C9 ALS diagnosis and her own genetic risk led her to pivot her research career toward curing it
06:41 The biology of the C9orf72 repeat expansion and how TDP-43 dysregulation links it to ALS and FTD
11:40 Therapeutic strategies targeting TDP-43 pathology in ALS and FTD
15:35 The state of biomarkers for ALS and FTD, and why C9-FTD trials lag behind ALS
22:08 How Yentli is lowering barriers for biomarker, cell line, and drug development through CureC9
30:40 Call for collaborators and where to follow Yentli 
32:59 Closing remarks
Find out more: CureC9

This week on The Genetics Podcast, we're re-airing our conversation with Eric Green, Founder and CEO of Trace Neuroscience, Co-Founder and Chief Scientific Officer at Maze Therapeutics, and Adjunct Clinical Assistant Professor at Stanford University School of Medicine. Patrick and Eric discuss Eric's transition from cardiology to entrepreneurship, the role of highly focused biotechs in creating precision therapies, and the development of high-impact gene therapies for people with amyotrophic lateral sclerosis (ALS). We're revisiting this episode following Trace Neuroscience's recent announcement that the first patient has been dosed with its antisense oligonucleotide (ASO) designed to restore UNC13A function in ALS.
Show Notes
0:00 Intro to The Genetics Podcast
02:03 Welcome to Eric, his background in cardiology, and how he got into biotech
06:23 Eric’s experience incubating and spinning out early-stage companies with Third Rock Ventures and developing Maze Therapeutics
09:13 Eric’s decision to transition from academia to the world of biotech
11:24 Building Maze Therapeutics and Eric’s focus on and genetic modifiers to discover new drugs   
15:09 The growth of therapeutic modalities in the context of genetics and gene therapies
16:48 What led Eric to launch Trace Neuroscience to develop ALS therapies
28:35 The process of getting Trace’s ALS therapies into the clinic
32:22 The identification of therapeutic value in low odds ratio genes
35:58 Eric’s view on the APOA1 gene target and its major effect size in kidney disease
40:03 How best to integrate genetics and genetic discovery into small and medium biotechs
41:50 Closing remarks
Find out more
Trace Neuroscience

https://www.businesswire.com/news/home/20260622451252/en/Trace-Neuroscience-Initiates-Global-Clinical-Development-Program-for-TRCN-1023-an-Antisense-Oligonucleotide-Designed-to-Restore-UNC13A-Function-for-the-Treatment-of-ALS

This week on The Genetics Podcast, Patrick is joined by Dr. Timothy Yu, Associate Professor of Pediatrics at Harvard Medical School and Physician/Researcher at Boston Children’s Hospital. They discuss how one child’s hidden genetic mutation led Tim into individualized ASO medicine, what it takes to develop n-of-1 therapies, and how new regulatory frameworks could expand treatment options for children with ultra-rare genetic disease.
Show Notes
0:00 Intro to The Genetics Podcast
01:00 Welcome to Tim
02:05 How uncovering the genetic mutation underlying an ultra-rare disease led Tim into personalized ASO medicine
07:38 Challenges in developing a custom ASO 
12:25 How Tim’s team has scaled individualized ASO therapies to reach more than 50 patients worldwide
16:18 Measuring clinical benefit in n-of-1 therapies with natural history data, wearables, and biomarkers
20:24 How the N-of-1 Collaborative helps rare disease researchers share infrastructure 
24:28 Comparing ASOs, base editing, and prime editing for individualized rare disease therapies
30:06 Finding scalable models for n-of-1 therapies in newborn genetic disease
33:52 The potential impact of the FDA’s Plausible Mechanism framework on bespoke therapies
36:58 Connecting rapid newborn genome sequencing to earlier treatment for rare genetic disease
42:10 Closing remarks