#268 ‒ Genetics: testing, therapy, editing, association with disease risk, autism, and more | Wendy Chung, M.D., Ph.D.

Episode Summary

Executive Summary: Peter Atiyah and Dr. Wendy Chung discuss the evolution of human genetics from pre-genome-era lab work to modern whole-genome sequencing, newborn screening, and gene therapy. They emphasize that genotype alone is often insufficient for clinical decisions, highlight the promise of population newborn genomic screening (Guardian), and explore the technical, ethical, and economic hurdles that still limit gene editing and therapy.

Main Topics: From pre-genome genetics to modern sequencing: Chung contrasts early manual PCR, linkage mapping, gels, and chromosome-by-chromosome work with today’s high-throughput sequencing, explaining how the Human Genome Project transformed discovery speed and collaboration. PKU as a model for newborn screening and gene therapy: Phenylketonuria is used to illustrate recessive disease, phenotype-genotype mismatch, lifelong dietary management, and why early detection via newborn screening prevents irreversible neurologic injury. Clinical genetic testing vs consumer genomics: Chung distinguishes targeted medical testing, exome/genome sequencing, and recreational SNP-based services like 23andMe/Ancestry, stressing that consumer tests do not provide a medical clean bill of health. Guardian study and genomic newborn screening: The Guardian study uses dried blood spots and genome sequencing to screen newborns for actionable conditions, aiming to improve equity, detect disease earlier, and adapt quickly as treatments emerge. Gene therapy and gene editing: promise and limits: The conversation covers viral vectors, delivery challenges, immune responses, CRISPR, prime editing, and why somatic correction is favored over germline enhancement or editing. Complex traits: obesity, autism, and cardiovascular disease: Chung explains that these conditions are highly heritable but polygenic and environmentally influenced, with many genes and pathways involved rather than a single causal mutation. Ethics, cost, and future of precision medicine: They discuss the high cost of current gene therapies, the need for scalable diagnostics, and the ethical boundary against germline enhancement, especially after the CRISPR controversy in China.

Key Arguments: Genetics is most useful when it starts with the patient and ends with the patient; research should directly improve clinical care. For PKU, genotype alone does not fully predict phenotype, so newborn screening combines biochemical and DNA-based data to improve accuracy. Consumer genetic tests are not equivalent to clinical sequencing and should not be used to make irreversible medical decisions without confirmatory testing. Many treatable childhood diseases are missed until years later; genomic newborn screening can identify them before damage occurs. Gene therapy is most promising for recessive loss-of-function disorders, especially liver-based metabolic diseases, because partial correction may be sufficient. Somatic gene editing is ethically acceptable for severe disease, but germline enhancement is broadly rejected by the scientific community. Obesity, autism, and cardiovascular disease are genetically influenced but usually involve many genes plus environment, so single-gene fixes are rarely sufficient. The biggest bottlenecks in gene therapy are delivery, fidelity, immune response, and cost—not just knowing the correct gene sequence.

Data Points: Clinical vs research time split: ~20% clinical / 80% research - Chung describes her work balance before taking on her new administrative role. PKU frequency in Ireland: ~1 in 5,000 - Estimated prevalence discussed as a rough figure. PKU frequency in the U.S.: ~1 in 10,000 - Chung gives a rough U.S. estimate. Human genome similarity: ~99.9% identical - Humans differ by about 1 in 1,000 base pairs on average. Coding DNA fraction: ~1.5% - Approximate portion of the genome that encodes proteins. Non-coding DNA fraction: ~98.5% - Large majority of the genome has regulatory or unknown function. Genome Project initial completion: ~70% of 3 billion base pairs identified in 2000 - Chung describes the early draft human genome. Estimated human gene count: ~20,000 genes - Current estimate contrasted with earlier expectations of 100,000. Genes with known disease associations: ~7,000 - Chung says functions/disease links have been assigned to about 7,000 genes. Whole-genome read depth: ~30x typical; up to 1,000x for cancer - Used to distinguish true variants from sequencing error and detect low-frequency somatic mutations. Guardian study enrollment: Just over 3,000 babies - New York City newborn genomic screening feasibility study. Guardian parental acceptance: ~74% - Proportion of approached parents who opted in. SMA newborn screening uptake: ~93% - Earlier screening program acceptance rate. Duchenne muscular dystrophy screening uptake: ~84% - Earlier screening program acceptance rate. U.S. newborns screened for SMA: ~4 million per year - Because SMA was added to recommended universal newborn screening. Guardian study cost per baby: ~$1,000 - Fully loaded cost including sequencing, interpretation, and staffing. Target cost per baby: ~$100 - Long-term goal for scalable genomic newborn screening. Rare genetic condition prevalence: ~10% of the U.S. population - Chung notes many people have a rare monogenic condition, known or unknown. Autism heritability: ~0.8 to 0.9 - Twin-study estimate across the spectrum. Autism prevalence: ~2% - Approximate current prevalence discussed. Obesity heritability: ~0.5 - Twin-study estimate for body mass index/adiposity. Type 2 diabetes heritability: Higher than obesity - Chung notes it is more strongly genetic than obesity. Major depression heritability: ~0.3 - Compared with higher heritability psychiatric conditions. Cardiomyopathy prevalence: ~1 in 500 - Example of a relatively common genetic heart disease. Gene therapy cost: ~$1 million to $3 million - Current range for approved gene therapies, including SMA around $3 million.

Pivotal Quotes: "It starts with the patient and ends with the patient." — Dr. Wendy Chung: Explaining how she integrates clinical care and research. "We don't exclude 100% phenylalanine, so it's a low-protein diet in general." — Dr. Wendy Chung: Describing lifelong PKU dietary management and why treatment is titrated. "We're not trying to create superhuman... we're not doing gene editing, gene manipulation to affect the next generation." — Dr. Wendy Chung: Clarifying the ethical boundary against germline enhancement.

Implications: Genomics is moving from diagnosis to prevention, but broad clinical impact depends on better interpretation, cheaper scalable screening, safer delivery systems, and clear ethical limits on germline editing.