Genomics and Health Outcomes (with Noor Siddiqui)
Spencer Greenberg speaks with Noor Siddiqui about the revolution in genetics research, driven by massive data aggregation, enabling the measurement of high-complexity genetic factors. They discuss ORCID's preconception and embryo screening services, which allow couples to mitigate genetic risks for common diseases in their future children.
Deep Dive Analysis
13 Topic Outline
The Revolution in Genomics: Parallels with AI
Old-School vs. Modern Genetics: Single-Gene vs. Polygenic
How Polygenic Risk Scores (PRS) are Calculated and Interpreted
Applying Genetic Technology in Reproductive Settings: Orchid's Mission
Preconception Screening and Embryo Selection via IVF
Future Reproductive Technologies: In Vitro Gametogenesis (IVG)
Ethical Considerations of Advanced Genetic Technologies
Orchid's Testing vs. 23andMe: Key Differentiators
Defining a Gene and Understanding 'Junk DNA'
Genetic Similarity Among Humans and Across Species
The Role and Implications of Epigenetics
The Future of Genetic Engineering: CRISPR and Gene Therapy
Moral Obligations of Parents Regarding Genetic Risk
7 Key Concepts
Genome-Wide Association Studies (GWAS)
These studies identify genetic variants associated with a disease by comparing the DNA of individuals with the disease (cases) to those without it (controls). They look for statistical associations between specific genetic markers and the presence of the condition.
Single Nucleotide Polymorphisms (SNPs)
SNPs are single-base differences in the DNA sequence that occur at specific locations in the genome. These millions of variations account for the genetic diversity between individuals, influencing traits and disease susceptibility.
Polygenic Risk Scores (PRS)
PRS are weighted linear models that aggregate the effects of thousands or millions of genetic variants (SNPs) to quantify an individual's genetic predisposition to complex conditions like heart disease or schizophrenia. The score is often expressed as a percentile, indicating relative risk.
In Vitro Gametogenesis (IVG)
IVG is a theoretical future technology that aims to create egg or sperm cells from any somatic cell in the body, such as a skin cell. This involves reprogramming the cell into a pluripotent stem cell and then directing its differentiation into a gamete.
Junk DNA (Regulatory DNA)
This term refers to the vast majority (about 98%) of the human genome that does not directly code for proteins. While once thought to be useless, it is now understood to be regulatory DNA, influencing when and how genes are expressed and impacting disease.
Epigenetics
Epigenetics involves modifications to DNA, such as methylation patterns, that affect gene expression without altering the underlying DNA sequence. These marks can turn genes on or off in response to environmental factors and can even be transferred from parents to children.
CRISPR
CRISPR is a gene-editing technology that allows for precise cutting and pasting of DNA sequences. It is a powerful research tool for making specific genetic changes and is being developed for gene therapies to correct single-gene mutations.
10 Questions Answered
The revolution in genomics, similar to AI, is due to drastically dropping costs of compute and storage, leading to the aggregation of massive datasets (over 150 million people sequenced by 2020), which allows for the identification of important genetic variants for common conditions.
'Old-school' genetics focuses on rare, single-gene disorders (like Huntington's), while 'modern' genetics uses large datasets to measure susceptibility for common, complex conditions (like heart disease or schizophrenia) driven by many genes.
Polygenic risk scores are weighted linear models derived from genome-wide association studies, where the presence of specific genetic variants (SNPs) is correlated with disease. An individual's score is then translated into a percentile, indicating their relative risk compared to the population average.
Orchid offers a preconception screen for couples using saliva samples to estimate their future child's genetic risk for common conditions. If high risk is identified, couples can choose embryo screening via IVF to select and transfer an embryo with the lowest genetic risk for the concerned condition.
Orchid focuses on future child's risk, sequences 100% of both partners' genomes (using NGS) to include millions of variants for polygenic risk scores, and provides physician-approved tests with genetic counselor support, unlike 23andMe which offers individual reports, sequences less than 2% of the genome (array-based), and is direct-to-consumer without medical oversight.
'Junk DNA' refers to the vast majority (98%) of the genome that does not code for proteins. While previously thought to be useless, it is now understood to be regulatory DNA, impacting which genes are transcribed and expressed, and has been found to be correlated with disease in genome-wide association studies.
Humans share 99.9% of their 3 billion DNA bases with every other human. When talking about siblings sharing 50% of DNA, it refers to the 4-5 million sites (SNPs) where individuals differ. Many biological processes and genes are also conserved across species, leading to high genetic similarity with animals like chimps.
Epigenetics involves modifications to DNA, such as methylation patterns, that affect gene expression without altering the underlying DNA sequence. These marks can turn genes on or off in response to environmental changes (e.g., starvation) and can even be transferred from parents to children, suggesting environmental influences can be inherited.
While technologies like CRISPR allow for cutting and pasting DNA, widespread genetic engineering to change traits like eye color in humans is currently far out. Gene therapies exist for specific single-gene mutations (like SMA), but challenges remain with delivery, safety, off-target effects, and the complexity of traits driven by many genes.
There's a framework of 'deserved vs. undeserved bad luck.' Parents now have the capability to forecast future risks and decide whether to mitigate 'undeserved bad luck' by reducing genetic susceptibility for their child, or to view it as 'rolling the dice' and accepting the natural genetic lottery.
12 Actionable Insights
1. Mitigate Child’s Disease Risk (IVF)
If a preconception genetic screen reveals high risk for a complex condition (e.g., schizophrenia) in a future child, couples can undergo IVF, sequence embryos, and select the embryo with the lowest genetic risk for transfer. This offers a unique opportunity to reduce the incidence of diseases running in the family.
2. Assess Future Child’s Genetic Risk
Couples can use services like ORCID’s preconception screen, which analyzes both partners’ saliva samples, to discover their future child’s estimated genetic risks for common conditions like heart disease, diabetes, and cancer before conception. This provides personalized information to inform reproductive decisions and potential mitigation strategies.
3. Quantify Family Genetic Risk
If you have a family history of a condition, utilize comprehensive genetic testing (sequencing 100% of the genome) to quantify your personal genetic risk and understand its potential contribution to your child’s risk. This offers a more complete picture than limited old-school genetic tests.
4. Prepare for Child’s Health Risks
If genetic testing identifies a high risk for a specific condition in your future child (e.g., type 1 diabetes), being alerted and aware of this risk ahead of time can lead to better health outcomes. This proactive knowledge can help avoid diagnostic delays and reactive responses to emerging symptoms.
5. Prevent Monogenic Diseases (IVF)
For couples identified as carriers for single-gene recessive conditions (e.g., cystic fibrosis), consider preimplantation genetic testing for monogenic defects (PGTM) during IVF. This allows for embryo screening to mitigate the risk of these rare, severe diseases.
6. Estimate IVF Mitigation Potential
Before undergoing IVF for genetic risk mitigation, use a preconception report to estimate how much risk reduction is possible based on the number of embryos you realistically expect to produce (e.g., less than eight embryos over a few cycles). This helps set realistic expectations for the process.
7. Ethical Parenting: Undeserved Bad Luck
When making reproductive decisions with new genetic information, consider the ethical framework of “deserved versus undeserved bad luck.” This can help parents decide whether to actively mitigate their child’s susceptibility to diseases that would constitute undeserved bad luck.
8. Leverage Analogies for Learning
Use analogies as effective teaching tools to quickly grasp new subjects, especially if you have a strong background in the analogous domain (e.g., programming for genomics). However, be cautious not to force analogies or use them for rigorous argumentation, as they may oversimplify or misrepresent nuances.
9. Improve Critical Thinking Skills
Utilize free, interactive programs on clearerthinking.org, such as the rationality test or common misconceptions game, to test and improve your critical thinking, decision-making, and habit formation. These tools are based on scientific research to shift behavior.
10. Quick Stress & Anxiety Relief
Download the free MindEase app (iOS, Android, web) to access scientifically proven, interactive exercises designed to relieve stress and anxiety in under 10 minutes. The app measures your state of mind before and after exercises to show what works for you.
11. Stay Informed with One Idea
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12. Engage with the Podcast
Share your thoughts and questions by emailing [email protected], leaving a voicemail at 321-341-4669, or rating and reviewing the podcast. This helps connect with the show and its creators.
5 Key Quotes
For you and me, our genetics are fixed. We can, you know, make lifestyle changes. We can do preventative screening to sort of stall out the onset of a lot of these diseases. But when you have a child, you have this really unique chance to reduce the incidence rate of a disease that's affected your family.
Noor Siddiqui
IVF has already been treating the diseases that gene therapy will one day treat for $20,000 a case as compared to millions of dollars a case.
Noor Siddiqui
We thought that these pieces of DNA that weren't in genes were useless, but we discovered through genome-wide association studies and in a bunch of other experiments that actually these regions are correlated with disease.
Noor Siddiqui
Our approach, despite I think what some people might think is actually pretty humble, right? Like right now during IVF, the embryo prioritization process is purely a beauty contest.
Noor Siddiqui
The human genome will revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases.
Bill Clinton
1 Protocols
Mitigating Genetic Risk for Future Children (Orchid's Process)
Noor Siddiqui- Couples submit a saliva sample for a preconception screen to discover their future child's risks for common conditions like diabetes, heart disease, cancers, and schizophrenia.
- If a couple identifies a high risk for a specific condition and wishes to mitigate it, they can elect to go through embryo screening via IVF.
- Each embryo created through IVF is sequenced to determine its genetic propensity for the concerned condition.
- The couple then elects to transfer the embryo with the lowest genetic risk for that specific condition, providing a mitigation option that was not previously available for complex diseases.