#268 ‒ Genetics: testing, therapy, editing, association with disease risk, autism, and more | Wendy Chung, M.D., Ph.D.
Dr. Wendy Chung, a board-certified clinical and molecular geneticist, discusses the evolution of genetics from pre-Human Genome Project to modern sequencing. She explores genetic testing types, the underpinnings of conditions like PKU, breast cancer, and autism, and the future and ethics of gene therapy.
Deep Dive Analysis
16 Topic Outline
Introduction to Dr. Wendy Chung and Her Work
Understanding Phenylketonuria (PKU) and Newborn Screening
Evolution of Genetic Research: Pre-Human Genome Project
Insights and Surprises from the Human Genome Project
Differentiating Genetic Tests: Commercial vs. Clinical
Whole Genome Sequencing and Mosaicism Explained
Genetic Testing for Breast Cancer Risk
The GUARDIAN Study: Genomic Newborn Screening
Gene Therapy: Historical Context and Current State
Gene Addition vs. Gene Editing: CRISPR and Prime Editing
Gene Therapy Targets: Tay-Sachs and Fragile X Syndrome
Genetics of Obesity and Epigenetics
Genetics and Heritability of Autism Spectrum Disorder
Genetic Factors in Cardiovascular Disease
Economic and Ethical Considerations of Gene Therapy
The Future of Clinical Genetics and Gene Editing
11 Key Concepts
Mendelian Condition
A condition caused by a single gene, often following predictable inheritance patterns. Phenylketonuria (PKU) is an example, where a single gene defect leads to a specific biochemical problem.
Positional Cloning
A method to identify a gene based solely on its location within the genome, without prior knowledge of its biological function or physiology. This approach was considered revolutionary and enabled the discovery of many disease genes.
Contigs
Contiguous sequences of DNA that are pieced together informatically from smaller, overlapping DNA fragments during genome sequencing. This process is like assembling a jigsaw puzzle to reconstruct the full DNA sequence.
Exome
The aggregate of all coding regions (exons) within the genome. While it represents only about 1.5% of the total DNA sequence, it contains the instructions for making proteins, which are critical for most biological functions.
Read Depth
The number of times a specific nucleotide position in the genome is sequenced. A higher read depth (e.g., 30x or 1000x) increases the accuracy and confidence in identifying true genetic variants versus sequencing errors, especially for rare mutations.
Germline Mosaicism
A condition where some cells in the germline (egg or sperm) carry a genetic mutation, while others do not, resulting in a 'mosaic' pattern. This can lead to a parent transmitting a mutation to offspring even if the mutation is not present in all their somatic cells.
Polygenic Risk
The cumulative risk of a disease or trait determined by the combined effect of multiple genes, each contributing a small amount. This contrasts with monogenic conditions caused by a single gene and is relevant for complex diseases like cancer, obesity, and cardiovascular disease.
Gene Addition Therapy
A gene therapy strategy where a missing or non-functional gene is added back into cells, often using a viral vector, to produce the necessary protein or enzyme. This approach is typically used for recessive conditions where a loss of function is the primary problem.
Gene Editing
A gene therapy strategy that involves making precise, in-situ corrections to existing genetic variants within the genome, rather than adding a new gene. This method aims to 'fix' the problematic gene directly, often by changing single base pairs or larger segments.
CRISPR-Cas9
A gene editing system that works by making a double-stranded DNA break to correct genetic variants. While powerful, this method can lead to some instability and off-target effects as the cell repairs the break, potentially introducing unintended genetic changes.
Epigenetics
Chemical modifications to the genome that affect gene regulation without changing the underlying DNA sequence. These dynamic changes, such as methylation, can vary over a person's life and by cell type, influencing gene expression.
9 Questions Answered
PKU is a recessive genetic condition that, if untreated, leads to intellectual disabilities due to the buildup of toxic byproducts from phenylalanine. It is treated with a lifelong diet restricted in phenylalanine, which prevents brain damage.
Before the Human Genome Project, genetic work was very manual, involving techniques like radioactivity and reading DNA ladders on gels. Scientists understood DNA structure and its role in making RNA and protein, but lacked comprehensive genomic maps and high-throughput methods.
A major surprise was that humans have only about 20,000 genes, far fewer than initial estimates of up to 100,000. The complexity of human biology was found to lie more in how these genes are reused and regulated (isoforms) rather than in a vast number of unique genes.
Direct-to-consumer tests are generally for recreational purposes, focusing on ancestry or non-medical traits by looking at specific single nucleotide polymorphisms (SNPs). Clinical genomic tests, such as whole exome or whole genome sequencing, are designed to answer specific medical questions, looking at a much broader range of genetic information for disease risk or diagnosis.
Germline mosaicism means that a parent's egg or sperm cells contain a mutation not present in all their other body cells. This allows for the transmission of a genetic condition to offspring even if the parent themselves does not fully express the condition.
The GUARDIAN study (Genomic Uniform Screening Against Rare Diseases in All Newborns) is a newborn screening program that uses genome sequencing from dried blood spots to identify treatable rare genetic conditions in babies. Its goal is to provide early diagnosis and intervention, adapting flexibly as new treatments become available.
Gene therapy typically uses modified viruses (vectors) to deliver new or corrected genes into cells, often targeting stem cells for long-term effect. Challenges include immune responses to the viral vectors (as seen in Jesse Gelsinger's case), ensuring precise delivery to the correct cell types, and achieving the right dosage without toxicity.
The heritability of obesity is estimated to be around 50%, indicating a significant genetic component, though environmental factors also play a large role. For autism, heritability is estimated to be approximately 80-90%, making it one of the most highly heritable psychiatric conditions.
The current scientific consensus is that gene editing should focus on treating existing diseases in somatic (body) cells, not on making changes to the germline that would be transmissible to future generations. The concept of 'enhancement' (e.g., making people taller or smarter) is generally considered a line not to be crossed due to unknown long-term risks and societal implications.
10 Actionable Insights
1. PKU Management: Phenylalanine-Restricted Diet
If diagnosed with PKU, strictly adhere to a phenylalanine-restricted diet to prevent toxic byproducts from accumulating and causing intellectual disabilities.
2. Seek Second Opinion for Genetic Decisions
Before making major healthcare decisions based on genetic test results, such as a mastectomy, always seek a second opinion to confirm accuracy and avoid irreversible actions.
3. PKU & Pregnancy: Strict Dietary Awareness
Pregnant women with PKU must be extremely vigilant about their diet and aware of all food product contents to protect the developing fetus from adverse effects.
4. Understand Commercial Genetic Test Limitations
Do not rely on commercial genetic tests (e.g., 23andMe, Ancestry.com) for medical diagnoses or an ‘all clear’ on health risks, as they are not designed for medical purposes.
5. Consider Targeted Genetic Testing for Cancer
If you have a family history of cancer or specific ethnic heritage with known genetic risks (e.g., Ashkenazi Jewish for BRCA), consider targeted genetic testing for cancer risk.
6. Consider Medical Genetic Testing for Family Planning
For family planning, consider medical genetic testing to assess the risk of passing on recessive conditions like Tay-Sachs or cystic fibrosis to future children.
7. Explore Newborn Genomic Screening (Guardian)
If available, consider participating in newborn genomic screening studies like Guardian, which identify treatable rare diseases early, enabling timely intervention.
8. Uphold Ethics: Avoid Germline Gene Editing
Support the scientific consensus against germline gene editing, which involves making genetic changes transmissible to future generations, to maintain ethical boundaries.
9. Uphold Ethics: Avoid Gene Enhancement
Adhere to the ethical principle that gene therapy should be used for treating disease and improving health, not for ’enhancement’ of human traits.
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To deepen your knowledge in health and wellness, consider subscribing to Peter Attia’s premium membership for exclusive content and benefits.
7 Key Quotes
It starts with the patient and ends with the patient.
Wendy Chung
Reading out the DNA sequence, we're good at, we're not perfect at.
Wendy Chung
The first gene that I cloned took eight years, the last gene I cloned took eight hours.
Wendy Chung
We're all 99.9% the same. About one in a thousand base pairs is what you and I probably differ by on average.
Wendy Chung
Cancer is at the heart of a genetic disease, but oftentimes not from the genes you're born with, but for the changes that happen over your life course.
Wendy Chung
The nice thing about a virus is it was designed by mother nature to infect our cells, right? So it's pretty good at being able to do that.
Wendy Chung
Enhancement is a line that people are, I hope, not crossing, that it really is about disease and being able to make people healthier as we're doing this.
Wendy Chung