The Genetics Podcast

Latest Episodes:

EP 131: The potential of somatic genomics in drug discovery and development with Jake Rubens Apr 18, 2024

Show notes

0:00 Intro
0:40 Jake’s experiences as a serial entrepreneur starting five companies with a basis in genomic science
5:30 Opportunities for research and drug development in the realm of somatic science
9:20 Somatic evolution and how it provides valuable insights into disease mechanisms
12:30 Advantages and disadvantages of studying germline genome-wide association studies (GWAS) versus somatic genomes for target and drug discovery
17:00 How germline and somatic mutations can complement one another when studying conditions like MASH, autoimmune disorders, infectious diseases, and more
21:10 The method behind obtaining and analysing tissue samples
24:00 The importance of high resolution for somatic variation
29:30 “The genetics superhero”: How somatic variations can rescue maladaptive germline mutations
32:00 How to obtain tissue samples of hard-to-reach areas of the body, like the brain
33:00 How somatic genome can increase the scale of DNA data available
36:00 Best practices for scientific entrepreneurship
44:50 Jake’s predictions for the next big breakthroughs in genetics and precision medicine
48:20 Closing remarks
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EP 130: Quarterly insights into noncoding variants and GWAS with Dr. Veera Rajagopal Apr 11, 2024

Show notes

Show Notes:
0:00 Introduction
1:20 How polydactyl mutations can inform research on non-coding variant mechanisms

The importance of low-affinity binding between transcription factors and targets
How these lessons can help us improve our understanding of drug and target discovery
See Veera’s January round-up for more information: https://www.gwasstories.com/p/january-2024-human-genetics-roundup

16:30 Long non-coding RNA (lncRNA) variants associated with the neurodevelopmental disorder (NDD) gene CHD2

An overview of the roles lncRNA play in the human genome
The discovery of a lncRNA deletion that is linked to a CDH2-mediated neurodevelopmental disorder
Insights into Angelman syndrome and a therapeutic design currently being used to treat it
See Veera’s February Roundup for more information: https://www.gwasstories.com/p/february-2024-human-genetics-roundup
Twitter thread from the original author of the study: https://twitter.com/VGaneshMDPhD/status/1755708315181744330

28:00 A non-coding variant explaining the high prevalence of Brugada syndrome in South-East Asians (one of Veera’s personal favourite stories)

See Veera’s January Roundup for more information: https://www.gwasstories.com/p/january-2024-human-genetics-roundup)

41:00 The future of large scale genome-wide association studies

A recent massive GWAS on type 2 diabetes clustering the variants of disease mechanisms
A recent paper published in Nature Medicine that shows differences in the lipodystrophy clusters between East Asians and Europeans: https://www.nature.com/articles/s41591-024-02865-3
How type 2 diabetes manifests differently across ethnic groups, potentially influencing personalised treatment strategies

55:20 Closing remarks
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EP 129: Patient advocacy for genetic ALS and FTD with Jean Swidler, Executive Director of End the Legacy Apr 04, 2024

Show notes

0:00 Introduction
0:45 Jean’s personal experiences with family members with genetic ALS
10:00 Jean’s thoughts on the barriers and facilitators to providing treatment for those with genetic ALS
13:20 Insights into C9orf72, a common genetic determinant of ALS, and how it can also be associated with FTD
16:10 Jean’s experiences as an active advocate for those with genetic ALS and FTD
20:00 The evening of the playing field between patient advocates and researchers, as well as the importance of hearing both voices
23:40 Future challenges and priorities facing End the Legacy and tying into Sano’s Light the Way study
29:00 The push towards broad scale genetic testing for neurodegenerative conditions and potential legal concerns for preventative screenings
33:00 Lessons learned from advocacy groups for other genetic diseases like Huntington’s disease, Parkinson’s disease, and more
39:00 Final thoughts on End the Legacy, patient advocacy, and a message to those living with and/or researching genetic diseases
For more information about End the Legacy, please visit: https://www.endthelegacy.org/
To learn more about Sano’s Light the Way study, please navigate to this page: sanogenetics.com/light-the-way
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EP 128: Parkinson’s disease and precision medicine with Drs. James Beck and Ignacio Mata Mar 28, 2024

Show notes

0:00 Introduction
1:05 Insights into the PD GENEration’s (a programme from the Parkinson's Foundation) milestones and progress points for the upcoming year
3:30 The shifting attitudes and perspectives of neurologists and healthcare workers at the PD GENEration
5:50 Insights into Nacho’s work with the genetics of Parkinson’s disease
10:20 Barriers and facilitators to increasing Latino representation in Parkinson’s disease research, including the return of results process in Latin America
17:30 The PD GENEration’s efforts to increase the participation of ethnic minority groups in genetic studies and research
24:15 How to effectively choose inclusive and accessible clinical sites in Latin America
30:10 Major genes implicated in Parkinson’s disease and the potential for prediction and prevention via screening programmes
36:30 The implications of environmental and genetic risk factors for family members of those living with PD
45:00 Promising programmes in PD research and clinical trials, such as Denali and Biogen’s joint effort to develop small molecule inhibitors of LRRK2
48:40 Best practices for community and patient engagement to speed up the process for clinical trials
54:30 Closing remarks
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EP 127: Insights into precision medicine, fatty liver disease, and minimally invasive diagnostic tools with Dr. Mazen Noureddin Mar 21, 2024

Show notes

0:00 Intro
0:25 Mazen’s lifelong commitment to furthering the field of precision medicine in liver disease research, fueled by a personal connection of his grandmother developing MASH cirrhosis
2:30 Breakthroughs in the field of metabolic dysfunction-associated steatotic liver disease (MASLD) since the beginning of Mazen’s career
5:30 The potential impact of Resmetirom, a new drug that could treat MASLD and MASH cirrhosis
8:45 Significant takeaways from 40+ investigational clinical studies of novel treatments for MASLD/MASH
12:00 Alternatives to biopsies and potential tools for early, non-invasive diagnosis
19:00 Genetic determinants and risk factors for fatty liver disease
20:30 How Mazen uses genetic testing in the clinic for his patients
25:50 The impact of “miracle” weight loss drugs such as GLP-1s on patients with liver disease
29:30 The importance of early intervention to prevent late-stage cirrhosis
33:00 How to tailor treatment to consider environmental and epigenetic factors that impact genetic penetrance for liver disease
36:00 Potential links between metabolism and neurodegenerative conditions
39:00 Upcoming developments in MASLD and MASH research
41:00 Mazen’s relationship with his father, both as a dad and as a teacher

EP 126: Patient-led research for ultra-rare disease drug development with Julia Taravella, Executive Director of Rare Trait Hope Fund Mar 14, 2024

Show notes

0:00 Introduction
0:25 Julia’s personal experience with ultra-rare diseases within her family
10:25 The importance of increasing accessibility to genetic testing across populations to learn more about ultra-rare diseases
14:00 The origin story of Rare Trait Hope Fund
23:50 Current research and next steps in developing potential gene therapies for aspartylglucosaminuria
32:20 How best to applykey insights and best practices to improve the approach to ultra-rare disease treatment development
38:30 Next steps for Rare Trait Hope Fund and how people can help with Julia’s mission
44:00 Julia’s advice for families who are advocating for rare disease research and therapy development
46:50 Closing remarks
For more information on Rare Trait Hope Fund, please visit: https://www.raretrait.com/.

EP 125: The future of UK Clinical Trial Policy: Innovation, integration, and game-changing legislation with Lord James O’Shaughnessy Mar 07, 2024

Show notes

0:00 Introduction
1:25 How Lord O’Shaughnessy became involved in scientific policy making and his path to writing the UK Commercial Clinical Trials Review.
04:05 How Lord O’Shaughnessy pivoted from education to a focus on life sciences
06:38 The biggest challenges Lord O’Shaughnessy faced during his time as Parliamentary Under Secretary for Health (2016-2018)
08:00 Navigating the health and care system through Brexit and the introduction of the General Data Protection Regulation (GDPR)
11:27 How the need for the UK Clinical Trials Review was identified and what challenges and issues brought the project to the fore
13:46 What the report found to explain the decline of clinical trials in the UK?
16:09 Bureaucratic challenges reducing the speed of approval and how best to balance frontline healthcare and research innovation
19:10 How best the National Health Service can support and resource research
21:50 The structural and cultural elements needed to integrate clinical research into the UK healthcare system
23:20 Accessibility of data for research purposes and the key legal and policy frameworks required to support it
26:24 How best to enable successful and safe access to frontline health data for the purposes of research
29:25 Public health emergency legislation as a model for data sharing that could power research into poorly understood conditions with high unmet needs
30:15 Building trust and transparency with the general public around using health data to support research
32:00 Key areas where the UK is excelling in research
34:28 How to ensure that research is fundamental to the healthcare system
36:01 Budgets to invest in innovation
38:35 The challenges of moving to preventative healthcare solutions
40:00 The long-term view of early-stage R&D vs. immediate frontline healthcare
41:44 Key observations on current data and healthcare policies
44:35 Closing remarks
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Please find here a link to the Wired article that Patrick references during this episode.

EP 124: How ReCode Therapeutics is pioneering tissue specific delivery of gene therapies for Primary Ciliary Dyskinesia with John Matthews Feb 29, 2024

Show notes

0:00 Introduction
01:10 How growing up in Malawi planted the seeds for John’s career in medicine and transition to therapeutic development
04:35 Why John focuses on rare diseases and conditions such as asthma
06:01 What has changed over the last decade in terms of treating and understanding asthma and the progress that genetics has enabled
07:31 What drew John to ReCode and the areas and projects the company is working on
09:20 How clinical loss of function in ciliary cells provides insights into the genetic causes of Primary Ciliary Dyskinesia (PCD) and drives development of relevant therapeutics
11:15 New frontiers: Restoring ciliary cells in subsets of cystic fibrosis and PCD caused by loss of genetic function
13:05 ReCode’s delivery platform: How the company is pioneering tissue specific delivery with lipid nanoparticles. For more reading on the Salford Lung study and the SORT-LNP platform, scroll to the bottom of the episode information.
16:50 Collaboration: How Sano and ReCode are working together to offer genetic testing to PCD patients to better understand the genetic mechanisms underlying the disease (thinkpcd.com), and what is currently know about the genetics of PCD
19:01 Situs inversus: Prevalence and PCD
20:33 What is currently known about PCD penetrance and inheritance patterns
21:25 Challenges and complexities of drug development in common vs. rare diseases
24:37 Key differences in running clinical trials: rare vs. common therapeutic areas
27:15 How rare disease-focused companies are using natural history data to reduce the need for placebos at clinical trial
30:52 The Liver Forum: the movement to pool natural history data across major clinical trials to provide large, high datasets
33:26 How innovative programmes in the UK are aiming to securely and ethically share data at scale
35:35 Looking to the future: How innovation lies in the ability to use genetics and secure data sharing as a guiding principle for rapidly developing and delivering new treatments
37:21 The importance of data sharing to enable preventative measures
37:43 The transformative power of registries and patient-owned data
41:10 Closing remarks
Explore these papers to learn more about the Salford Lung study and ReCode’s SORT-LNP platform:

EP 123: The ethics of newborn genome screening: Actionable insights and beyond with Holly Peay, Senior Research Scientist at the Research Triangle Institute Feb 22, 2024

Show notes

0:00 Introduction
0:50 Holly’s background and career so far
03:30 Complex decision-making and multiple risk factors: Family history, genetics, phenotypes and beyond
07:05 Changes within the last decade to help people make complex, sometimes subjective, healthcare decisions
09:20 Impact on people: The RTI’s mission and the Early Check Study
13:45 Newborn genomic sequencing and the ability to screen for 1000s of conditions with a single dry blood spot
15:40 The ethical translation of new technologies and their integration into complex decision-making
17:00 How parents decide if genomic testing is right for their child
20:46 The factors that play into parents choosing lighter levels of testing rather than more in-depth options
23:25 Actionable insights: Choosing type-1 diabetes as a single newborn genetic screening panel
25:25 The percentage of families that receive an actionable result from the genomic testing process
28:30 Linking screening programmes with clinical trials: How to approach adding new genes to screening panels as research evolves
30:55 The ethical challenges around providing families with opportunities to support clinical trials
33:32 The types of genes included in Early Check’s different newborn screening panels and how they were categorised
36:18 Addressing incomplete genetic penetrance and the non-binary nature of genetic conditions
39:41 Fragile-X: Pre-mutation information and the ethical importance of second consent
41:28 The limitations of using a single blood spot sample and the potential solutions
44:29 Closing remarks
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EP 122: Building genome-scale engineered cells for biotechnology with Leslie Mitchell, Co-founder and CEO of Neochromosome Feb 15, 2024

Show notes

Summary:
0:00 Introduction
01:01 How Leslie got into the field of synthetic biology and engineering, and her career journey so far
02:45 What Leslie accomplished during her postdoc and recent transformations in the field of genomics
05:57 The impacts of non-coding regions of the genome and the outcome of deletions
08:20 How long it takes to make chromosomes, what does it cost, and what can we expect from the future of chromosome engineering
10:03 The inspiration behind Neochromsome and Leslie’s transition to industry from academia
13:05 From understanding the fundamentals of the genome to identifying industrial applications for genome-scale engineering
16:46 Potential gene therapy applications for the NeoYeast and NeoVector products
19:10 The power of delivering to cells using a 10-150 kilobase payload compared with lentivirus vectors
20:05 An explanation of yeast as a compact genome with few introns
21:48 How Neochrosome has developed a genome-rewritten yeast designed for incorporating non-canonical amino acids into proteins
24:10 The challenges of identifying scalable solutions
25:27 The process behind constructing an entire synthetic chromosome
27:38 The different methods for assembling DNA
28:28 How to scale the chromosome construction process in terms of both throughput and length
30:54 The biggest barriers to a gene therapy application of this technology
32:35 The lessons learned from yeast and whether they also apply to mammalian cells
34:14 The potential application of these technologies that Leslie is most excited about
35:00 Closing remarks
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