The Genetics Podcast

Latest Episodes:

EP 161: How large language models can help build immunotherapies with Michelle Teng of Etcembly Ltd. Nov 14, 2024

Show notes

0:00 Intro to The Genetics Podcast
01:00 Welcome to Michelle
01:35 Explaining immunotherapy and its evolution over the past decade
04:10 Current insights on immunotherapy responders and the underlying factors driving varied individual responses
05:50 The latest generation of T-cell receptor therapies
08:53 The origin of the Long Term Survivor Study, its purpose and how it informs discovery of new T-cell receptor therapies
12:32 How Etcembly is characterising T-cells and antibodies in survivor profiles
15:00 Using machine learning to understand the immune system
18:44 The complexity of Human Leukocyte Antigen (HLA) and how it relates to differences in T-cell receptor biology
22:35 T-cell repertoires in Long Term Survivor Study participants
26:06 Training LLMs in immune system biology, data and more
27:54 Michelle’s work at Immunocore and how she’s applied her knowledge to grow Etcembly
33:02 Setting up a new company at the crossroads of the Covid-19 pandemic and the inception of LLMs and AlphaFold
35:54 Current bottlenecks in pre-clinical immunotherapy development
37:23 Michelle’s eldest daughter’s experience with an ultra-rare genetic disease and the founding of SynaptixBio
43:34 Utilising biobanks and registries to better understand ultra-rare disease presentation
47:05 The power and importance of patient parent groups for developing rare disease treatments
48:48 Closing remarks
Find out morewww.etcembly.io www.synaptixbio.com

EP 160: Artificial Intelligence, GWAS in Drug Discovery, and Career Insights with Dr. Eric Fauman, Executive Director and Head of Computational Biology in the Internal Medicine Research Unit at Pfizer Nov 07, 2024

Show notes

0:00 Introduction
1:30 The power of social media: How Eric published 10 papers based on ideas that he discussed on Twitter
5:50 Explanation of The Table of Everything, an internal database at Pfizer that catalogs nearly 20,000 human genes and their associated diseases and traits
13:20 How Eric’s team works to correlate genome-wide association study (GWAS) results to real biological phenotypes and outcomes
18:10 Introduction to protein quantitative trait locus (PQTL), including its importance in biological and genetic data
25:10 Examining the evolving bottlenecks in drug development and the challenges of validating genetic targets
28:30 Navigating the gap between genetic hits and biological understanding, and how AI or functional studies could bridge this in target discovery
32:20 Linus Pauling's mentorship of Eric and how he might react to AlphaFold2’s breakthroughs in structural biology
35:15 Eric's take on using AI and how he's experimenting with it on trusted datasets
41:00 An introduction to Mendelian randomization, as well as its strengths and limitations
47:00 How Eric uses the TOP Model (Talent, Opportunity, and Passion) to guide this career choices and path
52:00 Diversity and collaboration in genetics research and implementation
55:00 Closing remarks
Resources mentioned throughout the episode:Mendelian Randomization with Proxy BiomarkersPaper: Mendelian randomisation with proxy exposures: challenges and opportunities, I Rahu, R Tambets, EB Fauman, Kaur Alasoo (2024)Explores proxy biomarkers as a method to assess in vivo activity of a protein target.
Trait Colocalization and Causal GenesPaper: Integrative analysis of metabolite GWAS illuminates the molecular basis of pleiotropy and genetic correlation, CJ Smith, N Sinnott-Armstrong, A Cichońska, H Julkunen, EB Fauman, Jonathon Pritchard, Elife 11, e79348Demonstrates how traits with opposing effects on a genetic variant may suggest a causal gene sits between them
Metabolite Profiling in Human KnockoutsPaper: McGregor TL, Hunt KA, Yee E, et al. Characterising a healthy adult with a rare HAO1 knockout to support a therapeutic strategy for primary hyperoxaluria, Elife. 2020;9. Published 2020 Mar 24.
Community Workshop on Effector Gene StandardsPresentation: Watch on YouTube
TOP Model for Career GuidanceArticle: Grab the Helm: How to Take Charge of Your Purpose, Passion, Progress
The Table of EverythingOverview: Read more on Pfizer’s site
UK Biobank Protein QTL StudyPaper: Sun, B.B., Chiou, J., Traylor, M. et al. Plasma proteomic associations with genetics and health in the UK Biobank,Nature, 622, 329–338 (2023).
Eric’s First GWAS ContributionPaper: Shin SY, Fauman EB, Petersen AK, et al. An atlas of genetic influences on human blood metabolites, Nat Genet.2014;46(6):543-550.
Every Gene Ever Annotated (EGEA)Public Resource: View annotations on GitHub Nine reasons not to use eQTLs to identify causal genes from GWAS:Random Sequences Can Create Regulatory Elements

“~83% of random promoter sequences yielded measurable expression” - de Boer CG, Nat Biotechnol, 2020
“Recently evolved enhancers are formed predominantly by exaptation of ancestral DNA” - Villar D, Cell, 2015
“Extensive co-regulation of neighboring genes complicates the use of eQTLs in target gene prioritization” - Tambets R, et al., HGG Adv., 2024

Enhancer Variants and Buffering in Important Genes

“eQTLs at GWAS loci are more likely to point to genes with low enhancer redundancy not associated with disease” - Wang X, Goldstein DB, Am J Hum Genet., 2020
“GWAS and eQTL studies are systematically biased toward different types of variants” - Mostafavi H, et al., Nat Genet., 2023
“CNVs are buffered by post-transcriptional regulation in 23%-33% of proteins significantly enriched in protein complex members” - Gonçalves E, et al., Cell Systems, 2017

eQTL Data Limitations vs. Proximity Information

“cis-eQTL target genes are relatively poor indicators of ‘true positive’ causal genes” - Stacey D, et al., NAR., 2018
“When molecular QTL colocalization evidence was removed, we saw similar classification results” - Mountjoy E, et al., Nat Genet., 2021
“Key predictive features included coding or transcript-altering SNVs, distance to gene, and open chromatin-based metrics” - Forgetta V, et al., Hum Genet., 2022

EP 159: Engineering macrophages to tackle rare disease with Noam Baumatz of Noga Therapeutics Oct 31, 2024

Show notes

0:00 Intro to The Genetics Podcast
01:00 Welcome to Noam and discussion of his motivation to drive rare disease forward
03:00 Noam’s daughter Noga’s experience of rare disease, including an 8 to 12 month journey to diagnosis
05:10 How the experience of his daughter receiving a genetic diagnosis motivated Noam to take change into his own hands
10:12 How meeting other families impacted by rare disease led Noam to work on gene therapy for children living with primary immune deficiencies
12:33 How Noga Therapeutics is aiming to reprogram blood stem cells and the potential impact on rare diseases
15:22 Why it’s not yet possible to use the technology to correct gain of function mutations
17:42 How Noga’s program is aiding treatment of multiple primary immune deficiencies
22:25 The techniques the company uses in XLA to modify stem cells and enable expression of a functional copy of the BTK gene
26:30 Why gene therapies don’t always provide a comprehensive solution or cure
28:10 Bridging the gap between transformative therapies and the cost of delivering drugs to very small ultra-rare disease populations
34:41 Noam’s history working in traditional Chinese medicine
39:53 The importance of thinking holistically about health, from understanding g genetic root causes to considering how genes impact whole organ systems
43:15 The collaborative nature of the rare disease community and how parents who want to use their personal experience to further research and advocacy can connect with Noam
44:37 Closing remarks

EP 158: Research Roundup with Dr Veera: Discoveries in neurogenetics, evolution, cardiac arrhythmias, and more! Oct 23, 2024

Show notes

0:00 Invitation to The Genetics Podcast meetup
1:30 Intro to The Genetics Podcast
2:30 Welcome to Veera
3:20 The evolution on skin color in humans and their ancestors:Discussion on how a retrotransposon—often called a "jumping gene"—within the ASIP gene (agouti signaling protein) influenced the evolution of skin pigmentation in humans and their ancestors. ASIP, a paracrine hormone produced by skin cells, plays a key role in determining skin color.

Veera’s Substack Post: How a Jumping Gene Shaped Human Skin Color Evolution - https://www.gwasstories.com/p/how-a-jumping-gene-shaped-the-human
Original Research: Study by Dr. Po-Ru Loh and Dr. Steve McCarroll from the Broad Institute, published in Nature Genetics - https://www.nature.com/articles/s41588-024-01841-4

18:00 - An overlooked tau isoform could unlock an effective drug for Alzheimer’s diseaseExploration of big tau, an often overlooked isoform with unique properties that may make it a promising therapeutic target for tauopathies like Alzheimer's disease. The therapeutic mechanism is reminiscent of Casgevy, a gene therapy treatment used for sickle cell disease.Resources:

Veera’s Substack Post: The Big Tau: A New Hope for Alzheimer’s - https://www.gwasstories.com/p/the-big-tau-a-new-hope-for-alzheimers
Original Research: Study from Dr. Huda Zoghbi’s lab on how the big tau splice isoform resists Alzheimer’s-related pathological changes - https://www.biorxiv.org/content/10.1101/2024.07.30.605685v1

34:10 Protecting cortical neurons from herpes simplex virusAn international team of researchers, led by Jean-Laurent Casanova and Yi-Hao Chan at Rockefeller University, has discovered that tomoregulin-1 (TMEFF1), a neuronal membrane protein, protects human cortical neurons from herpes simplex viral infection. The gene responsible for producing TMEFF1 encodes a viral restriction membrane protein that prevents viruses from entering brain cells, offering potential therapeutic insights.

Veera’s Substack Post: Discovery of TMEFF1, a viral restriction factor in the human brain - https://www.gwasstories.com/p/discovery-of-tmeff1-a-viral-restriction
Original Research: Study by the Jean-Laurent Casanova Lab at Rockefeller University, Human TMEFF1 is a restriction factor for herpes simplex virus in the brain - https://www.nature.com/articles/s41586-024-07745-x

47:30 KCNB1 and a novel cardiac arrhythmia syndrome
A genetic investigation into cardiac arrhythmias has identified a new noncoding Mendelian disease mechanism stemming from a rare Mendelian disorder.

Veera’s Substack Post: De novo enhancer creation by a noncoding mutation - https://www.gwasstories.com/p/de-novo-enhancer-creation-by-a-noncoding
Original Research: A novel familial cardiac arrhythmia syndrome with widespread ST-segment depression. The authors note, “We believe this is the first description of an entirely de novo cryptic enhancer causing a Mendelian disorder.” - https://www.nejm.org/doi/full/10.1056/NEJMc1807668

57:40 - Genomes vs. exomesExploring the cost-effectiveness of whole genome sequencing compared to whole exome sequencing for gene discovery. This segment explores the long-standing debate over exomes versus genomes, highlighting challenges in studying noncoding variants and the value of each approach in the context of common versus rare diseases.

Veera’s Substack Post: Genomes vs. Exomes - https://www.gwasstories.com/p/genomes-vs-exomes
Original Research: Yield of genetic association signals from genomes, exomes and imputation in the UK Biobank - https://www.nature.com/articles/s41588-024-01930-4

1:10:00 Closing remarks
1:14:30 Outro

EP 157: Bridging genomics, business, and equity in healthcare access with Mark Taylor of LGC Group Oct 17, 2024

Show notes

0:00 Invitation to The Genetics Podcast meet up

1:30 Intro to The Genetics Podcast

2:25 Welcome to Mark

3:10 Introduction to the National Institute for Health Research (NIHR)

4:05 Mark’s roles with the NIHR in strategic partnerships

7:35 Challenges patients face in accessing NHS resources and the NIHR’s efforts to streamline availability

13:25 How to scale breakthroughs in precision therapies so they are widely accessible to patients across the NHS: Top-down vs. bottom-up strategies

17:00 Applying principles of cost consequence analysis to NHS strategy

17:45 Misconceptions regarding NHS financing and the allocation of funding for medical innovations

23:20 Best practices for working with under- and mis-represented populations to facilitate development of and access to medical innovations

29:45 East London Genes & Health and Born in Bradford: Two cases where deep engagement and trust building resulted in robust data collection and innovation

32:45 Insights into the D Cyphr Program (DNA, Children, Young People’s Health Resource) aimed at gaining population-level genomic data to address broader health issues such as mental health and diabetes
34:35 Closing remarks

EP 156: The Genetics Podcast In-Person Event! Oct 11, 2024

Show notes

We hope you will join us at our first (of hopefully many!) in-person podcast event! Please use this link to sign up.

EP 155: Adeno-associated virus as a delivery vector for genetic eye disease treatment, with Paul Wille of Abeona Therapeutics Oct 10, 2024

Show notes

0:00 Invitation to our first in-person podcast event

1:30 Intro to The Genetics Podcast

2:20 Welcome to Paul

2:53 Adeno-associated virus (AAV) biology and its advantages over other viral vectors

5:20 The gene therapy landscape and options for therapy development and delivery

6:49 The limitations of working with AAV to deliver gene therapy, including genome capacity and challenges with dividing cells

9:37 Why enormous bioreactors and huge volumes are necessary in the AAV manufacturing process

11:22 Why the eye is an ideal target for AAV gene therapy, and the potential of single-dose gene therapies

13:36 Advantages of AAVs in delivering therapies into multiple different cell types

15:17 Moving pre-clinical AAV delivered therapies into a clinical setting

17:52 How Abeona’s therapies aim to address different types of inheritance patterns

18:53 The current landscape of monogenic eye disease and Abeona’s approach to inherited eye conditions

21:38 Exploring current relationships between government, industry, and academia when supporting research for rare diseases

22:27 Paul’s transition from academia to industry

26:12 How the barrier between academia and industry is becoming more porous and bidirectional – and what that means for research

28:06 Paul’s enthusiasm for a cutting-edge area of precision medicine that has yet to gain mainstream attention
30:38 Closing remarks

EP 154: Pioneering early disease detection through wearable devices and regular monitoring with Dr. Mike Snyder Oct 03, 2024

Show notes

0:00 Introduction
1:00 Overview of Mike’s background and contributions to genomics and preventative medicine, as well as how he first became interested in deep data collection for health monitoring
4:20 The use of various tools, including smartwatches, blood tests, genetic testing, and more, to create a comprehensive view of an individual’s health
7:00 Using wearables to monitor chronic diseases, initiated by Mike’s personal experience with the Lyme disease
13:00 The prevalence of undiagnosed diabetes and the long-term health impacts of being in a borderline or prediabetic state
17:00 The benefits and shortcomings of polygenic risk scores in generating treatment models
19:00 The promise of integrating preventative medicine, wearable devices, and deep data into primary healthcare
25:00 Punctuated points of aging, where rapid changes in biological aging occur at specific and unique stages in a person’s lifespan
31:00 The potential of cell-free DNA in advancing cancer treatments
33:00 The lack of data and digital and biochemical markers for diagnosing and monitoring mental health and neurodegenerative conditions
36:40 The need to incite a cultural shift towards greater data awareness and proactive health monitoring
39:00 Final thoughts: The discrepancy between healthspan and lifespan
42:00 Outro
To learn more about Dr. Snyder’s work, explore his book Genomics and Personalized Medicine and his certificate programs offered through Stanford University:

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EP 153: How genomics is re-writing the taxonomy of disease with Lon Cardon, President and CEO of The Jackson Laboratory Sep 26, 2024

Show notes

0:00 Intro to The Genetics Podcast
01:00 Welcome to Lon
01:51 Lon’s involvement in the very first GWAS and what drew him to large-scale genomics research
03:32 Was moving away from candidate genes towards GWAS and data sharing initially a controversial idea?
05:25 What Lon believes has driven collaboration and data sharing within research communities
07:38 How and why Lon transitioned from academia to working for GlaxoSmithKline (GSK)
10:43 Why GSK was one of the largest initial investors in genetics and how the company came to have the largest genetics department in the world in the early 2000s
11:46 How the emergence of tens of thousands of biomarkers for genetic diseases has changed the way Lon thinks about the role of genetics in drug discovery
13:29 The future of genetics research and how much that path has diverged from expectations 20 years ago
18:14 The current challenge: From exquisitely precise genetics tools to clumsy phenotype predictions
19:45 Paradigm shifts in the taxonomy of disease
22:29 What it takes to reorganize the taxonomic definition and approach to diseases such as metabolic dysfunction-associated steatohepatitis (MASH)
24:22 The changes needed within biotech and pharma to fully harness the possibilities of genetics in drug development
26:18 What drew Lon to the Jackson Lab, how it has evolved, and what he’s been focused on for the past three years
31:02 The Jackson Lab’s new precision medicine and cancer program, plus future plans for the institute’s legacy
35:56 What Lon has learned about running an international organization and global scientific collaboration 37:30 Lon’s advice to early career scientists on up-and-coming fields and technologies
41:40 Closing remarks

EP 152: Unlocking the secrets of gene regulation with Nadav Ahituv, Director of the Institute of Human Genetics at UCSF Sep 19, 2024

Show notes

01:15 - Introductions
02:02 - How our understanding of the non-coding genome has evolved throughout Nadav’s career
04:56 - Our current understanding of non-coding genome grammar
07:40 - Is there a missing piece to the common variant, common disease paradigm?
10:25 - Introducing ultraconserved elements (UCEs) and human accelerated regions (HARs)
12:50 - Can a simple code explain changes in certain regions of the genome? Does this require “messier” solutions, such as large language models?
14:25 - The potential of machine learning
16:56 - Using CRISPR and non-coding elements to treat haploinsufficiency-caused pediatric diseases
20:19 - Nadav’s experience of starting a company
24:44 - How CRISPR A minimizes the risks associated with traditional CRISPR editing
26:04 - How engineering fat cells can starve cancer
32:08 - What’s on the horizon for Nadav’s lab?
34:52 - Bats as unlikely “superheroes,”, and what we can learn from their glucose levels
38:43 - The genetic differences between archaic humans, like Neanderthals and Denisovans, and modern humans
40:33 - Closing remarks

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