Question to Address
Here are some of the topics and questions I hope to address through the podcast:
Population Genetics and Disease Architecture
Genetic Architecture of Disease
- How many genetic variants are implicated in the most common diseases (that is, how genetically sparse should we expect them to be)? What are the necessary sample sizes to discover these variants?
- Will most common diseases be caused by common or rare variants? Can evolutionary biology help us determine this a priori?
- For case-control studies, what is the relationship between disease prevalence (K), the genetic sparsity of the disease (p), total heritability, and the sample size needed to construct a meaningfully predictive PGS?
Population Stratification and Missing Heritability
- Will high-coverage whole genome sequencing (WGS) help us discover the so-called “missing heritability”?
- Is regressing out the first N principal components of population stratification a good enough way of separating polygenic effects from confounding factors? What about LD score regression; is this a better solution?
- Within-family PGS studies are one of the best ways to control for population stratification as well as environmental effects (especially environmental effects that are passively genetically correlated, like genetic nurture). Additionally, within-family studies directly mirror PGD, in that embryos are like siblings, sharing a relatedness of 0.5, and polygenic scores are distributed via meiosis.
- Will within-family studies show that heritability estimates from twin studies are overestimates?
- Will within-family PGS ever approach SNP-based heritability estimates?
- How can we address lack of PGS portability across populations? Do we simply need biobanks in more diverse places?
Medical and Behavioral Genetics
- How useful would PGS-based medical risk stratification be if implemented? That is, how much more effectively could we allocate medical resources (screening, medication, etc.) and how many unnecessary medical procedures could we forego?
- In what sense do PGS get at causal variants? If PGS predict traits of interest, does this question really matter?
Genetic Correlations and Selection
- A priori, should we expect it to be possible to select against disease traits without adverse effects? That is, can we perturb a complex, multidimensional system like the human genome without throwing everything out of whack?
- In the context of PGD, does the fact that we’re selecting among embryos, rather than directly editing the genome, mean we have less reason to worry about this problem?
- How can genetics be used to inform nosology (the classification of disease)? For example, genetic correlations point toward a unitary genetic factor of psychopathology; should this influence how we categorize mental disorders, or is this committing the fallacy of reification?
Intuitions and Permissibility
- How does status quo bias affect our ethical intuitions around genetic technologies?
- Are preimplantation, prenatal, and postnatal genetic screening all equally ethically permissible? Are prospective parents morally obligated to do any of these things if they are freely available? How do our ethical intuitions about naturalness affect our answer to this question?
- Julian Savulescu provides a strong case for genetic selection/editing against disease with his principle of Procreative Beneficence. What is the best counter-argument to it?
- What are the best consequentialist and deontological arguments for and against genetic selection or editing for disease? For enhancement?
Enhancement and History
- What is enhancement? Is it wrong?
- Is selecting against an embryo with a particular disorder (say, Down Syndrome) a tacit devaluation of the lives of those who have that disorder?
- How do we reconcile the history of genetic selection with its modern potential for reducing suffering?
- Where do we draw the line between disease-prevention and enhancement?
Pleiotropy, Genetic Diversity, and the Precautionary Principle
- How should we evaluate the ecological risk associated with gene-drives? To reiterate a previous question, but on a larger scale: can we perturb a complex, multidimensional system (in this case, an ecosystem, not a human body) without wreaking havoc?
- Is genetic diversity an inherent good? For example, one might argue that just as crop monocultures are more susceptible to certain novel viruses, we humans too might be more susceptible to novel pathogens if we increase genetic homogeneity at key disease-related regions in the genome.
- Regarding pleiotropy and unintended consequences, should we follow the precautionary principle and assume that there is no free lunch vis-à-vis biology?
- Certain positive traits (e.g., creativity) are moderately genetically correlated with psychopathologies like schizophrenia and bipolar disorder.
- Would parents selecting against these psychopathologies also be indirectly selecting against traits like creativity? (This assumes that creativity is highly heritable.)
- Assuming that creativity is a public good, how do we reconcile this apparent asymmetry in incentives? That is, how do we solve the collective action problem of maintaining beneficial types of genetic diversity when prospective parents are incentivized to select against it?
Privacy, GINA, and Discrimination
- How do we deal with concerns about privacy and the ease with which genetic data can be de-anonymized?
- Will the Genetic Information Nondiscrimination Act (GINA) do enough to protect the individual, both in the employment and health insurance contexts?
- What sort of arrangement will intelligence agencies and direct-to-consumer genetic testing companies come to? (For example, FamilyTreeDNA shared data with the F.B.I.)
Embryology and Reproductive Medicine
- Realistically, in a round of IVF, what percentage of embryos will extract, implant, and come to term successfully? How does this vary with maternal and paternal age?
- What is IVF like for a mother, both mechanistically (i.e., what are the steps) and emotionally?
- How far away are we from chromosome, gamete, or whole embryo synthesis? What about iterated embryo selection?
- How will these technologies change what it means to be human?
- What is the transhumanist case for PGD?
Economics, Health Insurance, and Policy
- Which countries with nationalized healthcare would be willing to provide free IVF + PGD for mothers? Is this something we will see in the coming decades?
- How cheap would genotyping or WGS have to get for it to be a net economic positive, from a cost-benefit perspective?
- What does the public think of genomic technologies like gene-drives, CRISPR, and PGD? What percentage of people would be willing to use these technologies (via their medical practitioner) if they had the ability?