What is Phenylketonuria (PKU) and how is it managed?

PKU is a recessive genetic metabolic disorder where the body cannot properly process phenylalanine, an amino acid. If untreated, it causes intellectual disabilities. It is managed with a lifelong, phenylalanine-restricted diet, emphasizing early diagnosis through newborn screening to prevent severe neurological damage.

How did genetic science operate before the Human Genome Project?

Before the Human Genome Project (pre-2000s), genetic work was laborious and manual. Scientists used techniques like protein electrophoresis, enzymatic activity assays to identify conditions at the protein level, and linkage maps to crudely locate genes. DNA sequencing was manual and low-throughput, involving radioactivity and physical gel reading.

What is the difference between somatic and germline mutations, and how does mosaicism relate?

Somatic mutations occur after conception in body cells and are not passed to offspring. Germline mutations occur in egg or sperm cells and can be inherited. Mosaicism means some cells have a mutation while others don't. An individual can be a germline mosaic, meaning the mutation is in some reproductive cells and can be passed down, even if not present in all body cells of the parent.

How do whole genome sequencing (WGS) and whole exome sequencing (WES) differ?

WGS sequences all three billion base pairs of DNA (coding and non-coding regions). WES focuses only on the exome, the ~1.5% of the genome that codes for proteins. While WGS provides more complete data, WES is often a cost-effective shortcut, especially since most known disease-causing variants are in the coding regions.

What is the Guardian Study?

The Guardian Study (Genomic Uniform Screening Against Rare Diseases In All Newborns) is a large-scale population health initiative using genome sequencing on newborn dried blood spots. It screens for treatable rare diseases with immediate interventions available, aiming to rapidly adapt to new treatments and promote health equity by identifying conditions earlier, often a decade before typical diagnosis.

What are the primary challenges in current gene therapy, especially with viral vectors?

A major challenge is the immune response to viral vectors like adenoviruses, which can cause severe side effects or even death, as seen in Jesse Gelsinger's case. Finding the correct therapeutic dose is tricky because an immune response often prevents subsequent treatments. New, non-viral delivery systems, like lipid nanoparticles, are being explored to mitigate these issues.

How do gene addition and gene editing differ, and which is better for conditions like sickle cell anemia?

Gene addition involves introducing a new, functional gene into cells, typically for 'loss-of-function' diseases where a protein is missing. Gene editing directly fixes malfunctioning genes within the existing DNA. For sickle cell anemia, gene editing is preferred because simply adding a functional hemoglobin gene would lead to too much, still problematic, hemoglobin.

What are the ethical concerns surrounding gene editing, particularly regarding germline editing and enhancement?

The scientific consensus is to avoid germline gene editing (changes transmissible to future generations) and 'enhancement' (improving beyond normal human traits, like intelligence or athletic ability), focusing solely on treating severe diseases in somatic cells. The concern is the unpredictable long-term effects, potential for misuse, and societal implications of creating genetic disparities.

What is the heritability of autism and what factors contribute to its rising prevalence?

Autism Spectrum Disorder has a high heritability (0.8-0.9), but it's not 100% genetic due to factors like prematurity and de novo mutations. Its rising prevalence is largely attributed to changing diagnostic criteria, increased recognition (especially in underserved populations), and greater motivation to seek diagnoses for access to resources, rather than solely environmental factors or genetic drift.

What is the expected future of diagnostics and therapeutics in genetics by 2040?

By 2040, diagnosis is expected to be trivial due to falling sequencing costs and advancements in machine learning and AI, making it more accessible globally. The pace of therapeutic development is harder to predict, but there is optimism for catalytic breakthroughs that will scale gene therapies, although the challenge of affordability for widespread implementation remains significant.

Why is the liver often an easier target for gene therapy?

The liver is considered a relatively easy organ to target for gene therapy because it acts as the body's metabolic clearinghouse. Many genes involved in inborn errors of metabolism are expressed in the liver, and some common viral vectors and delivery systems are well-suited to reach liver cells effectively.

How is the cost of gene therapy compared to other medical treatments?

Current gene therapies are very expensive, ranging from $1 million to $3 million per treatment. While this is prohibitive for widespread use, it's argued that a one-time gene therapy offering decades of life extension in infancy, like for SMA, can be more cost-effective over a lifetime than prolonged treatments like chemotherapy for cancer.

Key Moments

268 ‒ Genetics: testing, therapy, editing, association with disease risk, autism, and more

Q: What is the difference between recreational genetic testing (like 23andMe) and medically targeted genetic testing?

Recreational tests focus on ancestry and non-medical traits like earwax type, not providing definitive health risk assessments. Medically targeted tests, on the other hand, aim to answer specific clinical questions, such as cancer risk (e.g., BRCA mutations) or carrier status for reproductive planning, often focusing on a specific panel of genes or the exome.

Peter Attia MD

Science & Technology5 min read156 min video

Aug 28, 2023|49,952 views|650|52

Peter Attia MD Dr. Peter Attia Early Medical The Drive Podcast The Drive Longevity Zone 2

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TL;DR

Revolutionary genetic advancements: from diagnostics and therapies to ethical considerations and future potential.

Key Insights

Genetic testing ranges from recreational (Ancestry.com) to medically targeted (PKU newborn screening), with varying depth and purpose.

The Human Genome Project revolutionized genetics, revealing around 20,000 human genes and emphasizing data sharing.

Gene therapy, particularly for conditions like SMA and certain metabolic disorders, holds immense promise despite high costs and delivery challenges.

Gene editing technologies like CRISPR offer precise corrections but face ethical debates, especially regarding germline modifications and enhancement.

Complex conditions like autism and cardiovascular disease have significant genetic components, but require multifaceted approaches combining genetics, environment, and lifestyle.

The 'Guardian Study' demonstrates the potential of broad genomic newborn screening to identify and treat rare diseases early, promoting health equity.

THE EVOLUTION OF GENETICS: FROM MANUAL LABELING TO AUTOMATED SEQUENCING

Early genetic work involved painstaking manual processes, using radioactivity and physical temperature cycling for PCR, which were laborious and low-throughput. The launch of the Human Genome Project in the early 1990s marked a pivotal shift, requiring the development of automated technologies to sequence billions of base pairs. This era transitioned from understanding individual protein structures, like those in sickle cell disease, to mapping entire genomes, fundamentally changing how scientists approached human disease and its genetic underpinnings.

THE HUMAN GENOME PROJECT: UNVEILING BIOLOGICAL COMPLEXITY

The Human Genome Project, completed around 2000, initially surprised scientists by revealing approximately 20,000 human genes, far fewer than the 100,000 previously estimated. Despite our nearly 99.9% genetic similarity, even single nucleotide differences can have profound effects. A significant portion of the genome is non-coding, with much of its function, particularly in gene regulation, still being elucidated. The project also championed data sharing, fostering a collaborative scientific environment that accelerated understanding of human health and disease.

THE SPECTRUM OF GENETIC TESTING: RECREATIONAL VERSUS MEDICAL

Genetic testing varies significantly in its purpose and scope. Recreational services like 23andMe and Ancestry.com focus on ancestry and non-medical traits, not providing comprehensive health screenings. Medically targeted tests, on the other hand, address specific health questions, such as carrier screening for conditions like Tay-Sachs or cystic fibrosis, and panels for cancer risk like BRCA1/2 mutations. Genomic tests, encompassing whole exome or whole genome sequencing, offer the most comprehensive view, examining thousands of genes for clinical insights, though interpretation remains a challenge for many regions.

PKU: A PARADIGM OF EARLY DIAGNOSIS AND INTERVENTION

Phenylketonuria (PKU), a recessive metabolic condition, serves as a cornerstone of newborn screening. If untreated, high phenylalanine levels lead to intellectual disabilities, but early diagnosis and a strict low-phenylalanine diet can prevent these devastating effects. Newborn screening initially relied on bacterial growth tests and later moved to mass spectrometry. The 'Guardian Study' is now integrating genomic sequencing to enhance PKU screening, providing dual data streams (phenotype and genotype) for increased accuracy and earlier, more precise interventions, highlighting the potential for widespread genomic screening.

GENE THERAPY: PROMISE AND PERILS

Gene therapy aims to correct genetic defects by introducing functional genes. Early attempts, like Jesse Gelsinger's case with ornithine transcarbamylase deficiency, revealed the significant risks of viral vectors (adenoviruses) triggering severe immune responses. While current approaches aim for safer vectors and earlier intervention (e.g., treating newborns with SMA before immune system development), challenges remain in dosage, delivery, and bypassing immune recognition. Conditions affecting the liver are considered more amenable to gene therapy due to the liver's accessibility and metabolic role.

GENE EDITING: PRECISION AND ETHICS

Gene editing, exemplified by CRISPR-Cas9, allows for precise correction of genetic variants within the genome, rather than just adding new genes. While revolutionary, CRISPR's reliance on double-stranded DNA breaks raises concerns about fidelity and off-target effects. Newer technologies like prime editing aim to improve precision by making single-stranded cuts. The ethical implications are profound, with a scientific consensus against germline modifications or genetic enhancements that would be transmissible to future generations. The infamous Chinese CRISPR babies incident, aiming to prevent HIV via CCR5 gene manipulation, highlighted the ethical boundaries and global need for responsible scientific conduct.

THE 'GUARDIAN STUDY': SCALING GENOMIC SCREENING FOR ALL NEWBORNS

The 'Guardian Study' (Genomic Uniform Screening Against Rare Diseases in All Newborns), led by Dr. Wendy Chung, is a groundbreaking initiative aiming to implement broad genomic newborn screening. By sequencing the genome from dried blood spots and focusing on treatable conditions, the study seeks to identify multiple rare diseases concurrently, offering real-time adaptability as new treatments emerge. Operating in New York City, it reflects diverse populations and aims to reduce health disparities, democratizing access to early diagnosis and intervention. Early results show strong parental support and successful identification of conditions missed by traditional screening.

COMPLEX DISEASES: AUTISM, OBESITY, AND CARDIOVASCULAR HEALTH

Many common chronic conditions, including autism, obesity, and cardiovascular disease, have significant genetic components but are often polygenic, involving multiple genes and environmental factors. Autism exhibits high heritability (0.8-0.9), with over 100 confidentially identified genes and potentially 1,000 more, many affecting brain development and function. Obesity also has significant heritability (~50%), influenced by both genetics and environmental factors, as seen in comparative studies of populations with identical genes in different environments. Cardiovascular diseases like FH and elevated Lp(a) are genetically linked, but therapeutic strategies, such as PCSK9 silencing, might target common biological pathways rather than individual genetic variants.

THE ECONOMICS OF GENETIC THERAPIES AND FUTURE OUTLOOK

The current cost of gene therapies, ranging from $1 million to $3 million, poses a significant barrier to widespread adoption. While health economists argue for the long-term value of life-saving therapies in infancy compared to end-of-life care, scalability for common conditions remains a challenge. The hope is for transformative breakthroughs, similar to the cost reduction seen in genome sequencing (from $1 billion to $1,000), which could make gene therapies more accessible. While diagnostic capabilities are expected to become trivial and widely available by 2040, the widespread penetration of complex genetic therapies is less certain, depending on technological 'step functions' and societal resource allocation.

ETHICAL DILEMMAS AND RESPONSIBLE INNOVATION

The immense power of gene editing necessitates careful ethical consideration. The scientific community largely agrees on treating somatic cells for disease without making changes heritable to the next generation, preventing 'designer babies.' The line between therapy and enhancement is crucial; using gene editing for traits like intelligence or athletic ability raises significant concerns due to unknown long-term risks and societal implications. While therapeutic applications for severe, untreatable diseases are widely supported, routine gene manipulation, especially in germline cells, remains a contentious area, highlighting the need for robust ethical frameworks and global consensus in light of medical tourism and varying international regulations.

Mentioned in This Episode

●Supplements

●Companies

●Organizations

●Books

●Studies Cited

●Concepts

●People Referenced

Heritability Estimates of Various Conditions

Data extracted from this episode

Condition	Heritability Estimate
Obesity	~0.5 (50%)
Type 2 Diabetes	>0.5 (more heritable than obesity)
Type 1 Diabetes	<0.5 (less heritable, complex interaction)
Autism Spectrum Disorder	~0.8-0.9 (80-90%)
Bipolar Disorder	~0.5-0.6 (50-60%)
Schizophrenia	~0.5-0.6 (50-60%)
Major Depression	~0.3 (30%)

Common Questions

Recreational tests focus on ancestry and non-medical traits like earwax type, not providing definitive health risk assessments. Medically targeted tests, on the other hand, aim to answer specific clinical questions, such as cancer risk (e.g., BRCA mutations) or carrier status for reproductive planning, often focusing on a specific panel of genes or the exome.

Topics

Newborn Screening Human Genome Project PKU Autism Genetics Obesity Genetics Cardiovascular Genetics Somatic Vs Germline

Mentioned in this video

organizationChildren's Hospital of Philadelphia (CHOP)

The institution where Jesse Gelsinger's gene therapy trial took place.

conceptCCR5 gene

A gene manipulated in China to try and prevent children from getting infected with HIV, a controversial gene editing case due to existing effective alternatives and germline modification.

conceptDuchenne Muscular Dystrophy (DMD)

A condition for which a newborn screening study was conducted, and a treatment was recently FDA-approved.

companyAncestry.com

A genetic testing service focused on family heritage and ancestral origins, able to identify blood relatives.

conceptAdenovirus

A common type of virus (causing the common cold) often used as a vector or delivery vehicle in gene therapy. It can trigger a strong immune response, as seen in Jesse Gelsinger's case.

studySpark Study

A large autism study run by Dr. Wendy Chung, which helped identify a case of autism resulting from undiagnosed PKU.

personRudy Leibel

A scientist who did pioneering work in identifying leptin and the leptin receptor through positional cloning methods, contributing to understanding body weight regulation.

conceptSevere Combined Immunodeficiency (SCID)

A problem where overwhelming infection can be fatal, but treatments like bone marrow transplant are available. The Guardian study has improved screening for SCID, identifying babies missed by traditional methods.

personPima Native Americans

A group studied for obesity genetics, showing that despite shared genes, environmental factors (access to calorically dense foods) significantly influenced obesity rates.

conceptApoE gene

A gene with three isoforms (2, 3, 4) where the ApoE4 isoform is associated with a much higher risk of neurodegenerative disease.

personDr. Wendy Chung

Guest on the podcast, chair of pediatrics at Boston Children's Hospital and faculty at Harvard Medical School, an MD and PhD who specializes in genetics and research.

conceptHuman Genome Project

An international scientific research project with the goal of determining the base pair sequence of human DNA, announced the year Dr. Chung started her MD/PhD program.

conceptFragile X Syndrome

An X-linked recessive condition caused by a trinucleotide repeat expansion, requiring a gene editing strategy to shrink the repeat size, with challenges in brain delivery and determining treatment window.

bookThe Double Helix

A book mentioned as a fascinating account of the discovery of DNA's structure by Watson and Crick, with other pivotal contributors.

studyFramingham Study

An epidemiological study mentioned as an example of long-term longitudinal follow-up, which is rare for studies on autism development into adulthood.

conceptSpinal Muscular Atrophy (SMA)

A neurodegenerative condition that used to be the most common genetic cause of death for children under 2, but now has FDA-approved gene therapies where early screening and treatment show significant positive outcomes.

company23andMe

A genetic testing company that provides ancestry and some health insights, but is not designed for comprehensive medical diagnoses.

organizationBoston Children's Hospital

A prestigious institution where Dr. Wendy Chung is becoming the chair of pediatrics.

conceptPhenylketonuria (PKU)

A recessive genetic condition, specifically an inborn error of metabolism, which if untreated, leads to intellectual disabilities but can be managed with a special diet.

drugCOVID-19 Vaccine (mRNA vaccines)

Refers to the mRNA vaccines developed rapidly during the COVID-19 pandemic, which utilized lipid nanoparticles as a delivery system for nucleic acids, offering lessons for future gene therapies.

conceptAgouti Mouse

A mouse model for obesity where the mother's folate intake during pregnancy affects the epigenetics and obesity of the progeny, demonstrating transgenerational effects.

conceptWilson's Disease

A condition leading to liver failure and the need for transplant, treatable with zinc to outcompete copper and prevent copper overload, highlighting that not all genetic diseases require gene therapy.

conceptOrnithine Transcarbamylase Deficiency

A urea cycle defect for which early gene therapy was attempted, leading to the tragic death of Jesse Gelsinger.

studyThe Guardian Study (Genomic Uniform Screening Against Rare Diseases In All Newborns)

A large-scale genomic newborn screening program in New York City that sequences parts of the genome to identify dozens or hundreds of treatable rare diseases in newborns, aiming for health equity and early intervention.

personJesse Gelsinger

A young man who tragically died in 1999 during an early gene therapy trial for ornithine transcarbamylase deficiency, due to an overwhelming immune response to the adenovirus vector.

conceptCRISPR-Cas9

A gene-editing system that acts as an Achilles' heel due to double-stranded DNA breaks, leading to instability and potential off-target effects.

conceptTay-Sachs Disease

A severe neurodegenerative condition caused by a missing enzyme, for which gene addition therapy delivered to the brain is a potential treatment, but current delivery methods are challenging.

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