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

This week on The Genetics Podcast, Patrick is joined by Dr. Cara Altimus, CEO of BD², and Dr. Benjamin Neale, Associate Professor at Harvard Medical School and Massachusetts General Hospital. They discuss how rare variant discovery is opening new routes into bipolar disorder biology, how BD² is combining genetics with longitudinal multimodal data, and how patient priorities are shaping a research model focused on faster diagnosis and more precise treatments.

Show Notes

0:00 Intro to The Genetics Podcast

00:58 Welcome to Cara and Ben

01:57 The origin and aims of BD2 

04:20 Major knowledge gaps in bipolar disorder genetics

06:43 Using genetics and deep phenotyping to map bipolar disorder biology

13:47 Why bipolar disorder genetics needs both scale and deep clinical data

17:32 Finding the most predictive data for bipolar disorder biology and care

19:19 The search for scalable biomarkers in bipolar disorder

21:35 How BD² is building a bridge from discovery to clinical trials

26:48 Why bipolar diagnosis takes years and what patients want research to solve

33:08 How BD² is looking to other programs as inspiration to build a new research model

35:31 What overlapping risk genes reveal across bipolar disorder, schizophrenia, and autism

37:40 How rare variants could de-risk precision psychiatry trials

41:25 How BD² is scaling from early milestones to global funder momentum

45:04 Closing remarks 

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https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Find out more:

• BD2
  

This week on The Genetics Podcast, Patrick is joined by Dr. Angela Bradshaw, Director for Research at Alzheimer Europe and honorary lecturer at the University of Glasgow. Following a series of recent episodes exploring Alzheimer’s disease research, we’re revisiting this conversation to bring in an essential patient advocacy and nonprofit perspective on the field. Patrick and Angela discuss how Alzheimer Europe partners in and supports pan-European dementia research, the heterogeneity of dementia and Alzheimer’s disease, the future of potential new gene therapies, and the critical role advocacy organizations play in ensuring research reflects the needs and priorities of patient communities.
Show Notes

0:00 Intro to The Genetics Podcast

01:27 Welcome to Angela and how she joined Alzheimer Europe

06:06 The biggest priorities and areas of focus for dementia and Alzheimer’s Disease (AD) research

10:10 Biomarkers for dementia and how early in disease development they can be utilized

12:40 The heterogeneity of dementia and AD and current understanding of subtypes and treatment journeys

17:20 The challenges of diagnosis, early identifiers, and the integration of genetics

18:53 Angela’s view on the latest breakthrough therapies

22:50 Partnering in and supporting dementia research efforts across 30+ European countries

29:15 Reimbursement frameworks and shared regulations across different countries

33:40 Angela’s thoughts on the near future of gene therapies for AD and dementia

38:04 Why Angela spent 50 hours travelling the length of Australia by bus

41:26 Closing remarks

Find out more

• Alzheimer Europe

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This week on The Genetics Podcast, Patrick is joined by Salvador Rico, Chief Medical Officer at Encoded Therapeutics. With Encoded’s Dravet syndrome gene therapy program recently reaching major clinical and regulatory milestones, we’re revisiting this conversation on Salvador’s journey into drug development, his work on gene therapy for X-linked myotubular myopathy, and the fundamental challenges and exciting advances shaping the future of genetic medicine.

Show Notes

0:00 Intro to The Genetics Podcast

01:27 Welcome to Salvador and how he became involved in drug development

11:29 Frustrations and rewards of the genetics field

14:27 Salvador’s study on gene therapy for patients with X-linked myotubular myopathy (XLMTM)

20:13 Risk of liver issues in gene therapy trials and attempts to mitigate them

24:50 Encoded Therapeutics‘ approach to drug discovery and what motivated Salvador to join the team

27:50 Steps towards therapeutic targeting of gene regulatory elements 

30:32 Advantages of different methods for drug delivery 

32:59 DNA- versus RNA-based therapy

35:24 Insights from approaches in other fields, including psychiatry

37:03 Considerations for using natural history studies

41:00 Expectations and goals for Encoded Therapeutics’ current and upcoming studies

43:45 Closing remarks

Find out more

• Encoded Therapeutics

• New clinical data

This week on The Genetics Podcast, Patrick is joined by Dr. Vincent Dion, Group Leader at the UK Dementia Research Institute at Cardiff University. They discuss how repeat expansions drive Huntington’s disease and other neurological disorders, why DNA repair can sometimes worsen these mutations over time, and how CRISPR nickase editing could offer a new way to shrink disease-causing repeats rather than simply silence them.

Show Notes

0:00 Intro to The Genetics Podcast

01:00 Welcome to Vincent

01:45 Working on origins-of-life chemistry in Stanley Miller’s lab

03:56 Vincent’s path to genetics 

06:00 How somatic repeat expansion drives Huntington’s disease 

09:40 Therapeutic strategies for Huntington’s disease

15:29 Using gene editing to shrink repeat expansions

18:31 Optimizing CRISPR nickase delivery and expression for repeat expansion editing

25:15 Moving gene editing from academic research toward a first-in-human trial

27:31 Clinical trial challenges for Huntington’s gene therapies and uniQure’s early data

30:47 Epigenetic regulation of repeat instability in neurodegenerative disease

33:14 How basic science breakthroughs like CRISPR become transformative biology tools

34:55 How academic couples navigate the two-body problem when building research careers

39:39 Developing biomarkers to measure whether DNA-targeting therapies are working

42:17 Closing remarks

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This week on The Genetics Podcast, Patrick is joined by Dr. Paul Valdmanis, Associate Professor at the University of Washington. They discuss the impact of APOE4 on risk in Alzheimer’s disease, how long-read sequencing is uncovering hidden genetic variation in Alzheimer’s and ALS, and what rare variants and cryptic splicing can teach us about neurodegeneration.

Show Notes

0:00 Intro to The Genetics Podcast

01:00 Welcome to Paul

01:40 Long-read sequencing and ancestry-specific APOE4 risk in Alzheimer’s disease

04:20 Key findings from Paul’s study on a protective APOE4-linked variant in Alzheimer’s disease

10:58 What rare PSEN1 and PSEN2 variants reveal about Alzheimer’s disease biology

14:38 Disease-specific genetic mechanisms in ALS versus Alzheimer’s

17:14 Precision therapies for neurodegenerative disease

18:35 Choosing therapeutic targets in the neurodegenerative disease cascade

20:21 Landscape of ALS and Alzheimer’s therapies 

23:48 Lessons from liver-directed gene therapy on microRNA toxicity, cancer risk, and brain delivery challenges

29:12 Using long-read sequencing to uncover tandem repeat expansions missed by conventional genomics

33:26 Findings from a study of long-read sequencing on ancient genomes

38:06 Closing remarks

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https://drive.google.com/file/d/1Bp2_wVNSzntTs_zuoizU8bX1dvao4jfj/view?usp=share_link

Find out more:

• APOE study

• Ancestry study
  

This week on The Genetics Podcast, Patrick is joined by Dr. Bin Yu, CDSS Chancellor’s Distinguished Professor at UC Berkeley. They discuss how different statistical approaches, from linear models to random forests, can be used to study complex genetic traits, recent findings on epistasis in cardiomyopathy, and how improving robustness and reproducibility can lead to more reliable scientific conclusions.

Show Notes

0:00 Intro to The Genetics Podcast

01:00 Welcome to Bin

01:47 Linear models as the foundation of genetic analysis

05:34 Using random forests and stability to identify gene–gene interactions beyond linear models

11:05 How iterative feature weighting in random forests improves detection of gene interactions

13:10 Using GWAS to prioritize features in high-dimensional genetic data

15:06 Applying stable interaction models to hypertrophic cardiomyopathy in UK Biobank

20:47 Biological insights from gene–gene interactions in cardiomyopathy and evidence for indirect epistasis

23:25 Scaling discovery of epistatic interactions with better data and integrated experimental validation

27:21 The predictability, computability, and stability (PCS) framework for data science

30:06 How Bin’s early life during the Chinese Cultural Revolution shaped her 

32:54 Balancing AI-driven productivity with human reasoning and scientific thinking

35:23 Developing the ability to read people through observation, listening, and real-world interaction

38:03 Closing remarks

Find out more:

• Epistasis in cardiac hypertrophy study

• https://vdsbook.com/

This week on The Genetics Podcast, Patrick is joined by Dr. Sarah Marzi, Senior Lecturer at King's College London and group leader at the UK Dementia Research Institute. They discuss the impact of genes and environment on neurodegenerative disease, including: how APOE genotype shapes microglial function, how cell type-specific epigenomics of postmortem brain tissue is revealing the role of microglia and oligodendrocytes in Alzheimer's disease, and how pesticide exposure drives selective dopaminergic neuron loss and neuroinflammation in Parkinson's.

Show Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Sarah

02:13 Environmental contributions to Parkinson’s disease and ALS

05:01 The role of microglia in Alzheimer’s disease and findings from a study on APOE variants in a mouse model

12:50 APOE4 effects on lipid accumulation, microglial activation, and vitamin D receptor signaling 

14:20 Building a multi-omic atlas of the Alzheimer’s brain

18:01 Overview of the pathological cascade of events in the Alzheimer’s brain

20:31 Anti-amyloid therapies, early intervention, and combination treatment strategies 

22:24 Rotenone exposure and microglial immune activation in Parkinson’s disease

29:24 Dopaminergic neuron vulnerability to pesticide exposure and mitochondrial dysfunction 

31:04 Familial Parkinson’s genes, polygenic Alzheimer’s risk, and genetically targeted clinical trials

33:13 Polygenic risk and microglial cell state regulation in Alzheimer’s disease

34:13 Defining cell states in single cell RNA sequencing

35:30 Oligodendrocyte epigenetic and transcriptional changes in Alzheimer’s disease

37:23 Sarah’s most memorable hiking adventures

38:58 Closing remarks

Find out more:

• Alzheimer’s APOE microglia xenotransplantation study

• Rotenone exposure Parkinson’s study

This week on The Genetics Podcast, Patrick is joined by Lindsey Wahlstrom, Co-Founder and Chief Momatologist of Rona’s FUN LAB, Jimi Olaghere, sickle cell disease patient advocate and early CRISPR gene therapy trial participant, and Rachel Smith, Vice President and Head of Rare and Genetic Diseases at Parexel. They discuss the realities of developing and delivering advanced therapies in rare disease, how funding models, regulation, and trial design shape access and outcomes, and why embedding patient experience early is critical to building therapies that are not only effective but scalable, accessible, and meaningful for patients and families.

Show Notes: 

0:00 Intro to The Genetics Podcast

01:00 Welcome to guests and what Rare Disease Day means to them

08:09 Balancing hope with funding, pricing, and access in advanced therapies

11:48 Why patient access must be built into drug development from day one

14:20 Patient engagement, community readiness, and the realities of trial participation

17:49 Why early patient input is still inconsistent and often treated as a checkbox

23:20 Designing trials around what actually matters to patients and families

26:53 Navigating regulators, payers, and trial design constraints in rare disease therapies

36:02 Redefining success in gene therapy around access, scalability, and real patient benefit

43:27 Closing remarks