L6 Ethics Ethics and Genetics

Overview

This lecture traces genetics ethics across three eras and closes by naming the values that collide in real cases. It moves from the eugenics movement’s coercive use of “science” to classify and control people, through the genomics era’s growing complexity and commercialisation, to gene editing’s shift from reading DNA to rewriting it, and ends by showing how autonomy, family/group identity, equitable access, support for affected people, equality, and cost all pull against one another in concrete case studies.

Past: eugenics and dehumanisation

Eugenics was framed by its own advocates as “the self-direction of human evolution,” a movement drawing material from many fields (physiology, biology, genetics, psychology, mental testing, anthropometry, history, geology, archaeology, anthropology, statistics, politics, law, economics, genealogy/eugenics, sociology, religion) and applied through medicine, surgery and psychiatry.

• United States: mass “mental testing” programmes and propaganda displays classified people by supposed social worth. One display board carried the statement “Some people are born to be a burden on the rest,” and alongside it separate statistical panels: one stating that a person is born in the United States every 16 seconds (a light flashed at that interval), and another stating that a “high grade person” who will contribute to leadership is born every 7.5 minutes. The 16-second figure is a general US birth rate panel, not a rate for the “burden” category. Such classification targeted people labelled, for example, “feeble-minded.”
• Nazi Germany: Joseph Goebbels (1938) stated the regime’s objective was “a healthy people,” explicitly rejecting feeding the hungry or clothing the naked as a starting point. Record-keeping (ledger books) tracked hereditary status. Propaganda claimed a “hereditarily ill” person cost the state on average 50,000 Reichsmark by age 60, illustrated by a healthy man shown carrying disabled/ill figures on his back.
• New Zealand (1928): Parliament debated a law to let a committee of government employees and doctors authorise sterilisation of people labelled “feeble minded,” “unfit,” “degenerates,” “imbecile children,” or having “mental defects.” Per historian Hamish Spencer, the law had broad support among politicians, medics, the judiciary, several women’s organisations and academics, and would likely have passed had government pushed harder — but the sterilisation provisions did not pass.

[slide does not elaborate the specific ethical issues raised by eugenics or how they were addressed/learned from — this was left as an open discussion prompt]

Present: the Genome Project and genetic complexity

Clinical genetics timeline (2nd half of 20th century):

• 1950s: karyotyping identified trisomy 21 as the cause of Down syndrome.
• 1960s: non-directive genetic counselling adopted as the standard approach.
• 1970s: amniocentesis and chorionic villus sampling (CVS) developed.
• 1980s: amniocentesis/CVS increasingly offered as part of routine prenatal care.
• Gene-linkage research (e.g. mapping a breast cancer susceptibility gene to chromosome 17q21) fed into the Human Genome Project, whose completion was announced in the popular press (Venter and Collins, 2000) as “cracking the code.”

Falling costs, rising infrastructure: The cost of sequencing a human genome fell from roughly $100,000,000in2001tounder$1,000 by 2015–2022 — a decline far steeper than the Moore’s Law reference trend, especially after about 2007–2008. Resources such as ClinGen (NIH-funded) now curate the clinical relevance of genes and variants for precision medicine, with curation volume growing substantially from 2014 to 2023.

More testing, more complexity, not more certainty: We can now screen for or diagnose far more conditions than a decade ago, but results vary along several axes:

• high risk ↔ low risk
• certain ↔ uncertain
• lethal ↔ mild impairment
• treatable ↔ not-treatable
• child ↔ adult onset
• disease ↔ non-disease

The slide states “OGOD = unusual” while “uncertainty and complexity = common” (“we are building the plane, as we’re flying it”). [slide does not expand the acronym OGOD] Professional guidance has to keep pace: ACMG recommendations for reporting secondary/incidental findings from clinical exome/genome sequencing are periodically revised (e.g. version 3.2 added three genes — CALM1, CALM2, CALM3 — relative to 3.1, with none removed between those versions, while NTRK1 had been removed in an earlier update), and cover a wide range of actionable conditions (e.g. BRCA1/BRCA2 breast-ovarian cancer, Brugada syndrome, arrhythmogenic cardiomyopathies, dilated cardiomyopathy, biotinidase deficiency, familial thoracic aortic aneurysm).

Variable impact on people: People differ in how much genetic information they want and when they want it. Overall, the psychosocial impact of genetic results has been less dramatic than anticipated, but the same type of result affects different people differently, and most people need help interpreting results — more results mean more complexity, more interpretive/counselling work, and possibly more follow-up care.

Ethical flashpoints in the present era:

• Predictive testing decisions can go either way: Angelina Jolie publicly disclosed a BRCA-informed preventive mastectomy, while research on Huntington’s disease (the PHAROS study) found that rates of testing for the Huntington’s mutation were lower than predicted, with people giving reasons for declining.
• Research on ethnic/indigenous groups has been controversial: an Otago Daily Times front page ran “Warrior gene link in Maori violence” over a New Zealand study described as having controversial findings, and the Havasupai Tribe diabetes-research case became “a cautionary tale” about genetic research on indigenous communities. The slide prints no gene symbol; the transcriber renders the gene as “MAOI-A”, which is background identification rather than slide content.
• Commercialisation: at-home genetic testing kits, marketed newborn/child genetic testing (“BabyGenes”), and personalised-health marketing (e.g. “myDNA”) have expanded consumer access.
• Non-invasive prenatal testing uses fetal DNA fragments circulating in maternal blood to detect conditions such as trisomy.
• Privacy/geopolitics: a prenatal test developed with the Chinese military (BGI) was reported to have collected genetic data from more than 8 million women globally, using leftover blood samples for population research — viewed by the US as a national security threat.
• Visionary claims: Francis Collins (NIH Director, 2014) predicted that cheap DNA sequencing would lead to every baby’s genome being sequenced to personalise disease prevention, detection and treatment across a lifetime. Anne Wojcicki (23andMe) described testing her son at birth and her daughter’s amniotic fluid prenatally, framing genetic testing as “a responsibility if you are having children.”

Future: from “reading” to “editing”

CRISPR-Cas9 mechanism (targeted genome editing):

1. A guide RNA paired with the Cas9 protein locates a PAM sequence adjacent to a matching sequence in the genomic DNA.
2. Cas9 cuts the genomic DNA at that site.
3. The cut is repaired, incorporating a piece of donor DNA into the genome at the target site — replacing or inserting the desired sequence.
   This has been demonstrated across human cells, zebrafish, and bacteria.

Continuum of intervention points: genetic testing/editing decisions can apply across the human life course — embryo selection (e.g. at the 8-cell stage), prenatal testing, childhood, adulthood, and old age.

Rapid public and scientific reaction: Popular media framed CRISPR as transformative and unsettling (WIRED’s 2016 “Genesis Engine” cover described editing DNA as “now as easy as cut and paste”; Science named CRISPR its 2015 Breakthrough of the Year; MIT Technology Review declared “we can now engineer the human race”; TIME covered “the gene machine”). A Science “Perspectives” article by a large group of scientists (Baltimore, Berg, Botchan, Carroll, Charo, Church, Corn, Daley, Doudna, Fenner, Greely, Jinek, Martin, Puck, Sternberg, Weissman, Yamamoto), titled “A prudent path forward for genomic engineering and germline gene modification,” argued that a framework for open discourse on using CRISPR-Cas9 to manipulate the human genome is urgently needed, noting current applications already included correcting genetic defects (e.g. replacing a mutated gene underlying a liver-based metabolic disease in a mouse). [slide gives no publication year]

The title turns on a distinction the rest of the lecture relies on: somatic gene modification edits the DNA of a person’s body cells, so the change affects only that patient (the Victoria Gray sickle cell trial is somatic editing), whereas germline gene modification edits gametes or embryos, so the change is heritable and passes to future generations. [slide does not elaborate the distinction beyond naming both in the article title]

Governance response: the International Summit on Human Gene Editing, “a global discussion,” was held in Washington, D.C., 1–3 December 2015. The slide also shows a photograph taken at the SECOND INTERNATIONAL SUMMIT ON HUMAN GENE EDITING, of a man speaking at the lectern, identified by conference context as He Jiankui. [slide does not elaborate on what He Jiankui did or on the second summit’s date or outcome]

Ethical dilemma framing: an Atlantic article asked whether editing a baby’s genes could become mandatory, predicting that within the author’s lifetime parents might be prosecuted for refusing to edit their unborn child’s genes. [flag: the slide prints the byline date as “Apr 14, 2014,” though the article is widely dated 2017 — transcribed exactly as shown on the slide]

Ethical commitments in tension

The lecture names six ethical commitments that recur in genetics and often conflict with one another:

• Respecting individual autonomy
• Recognising familial, tribal and genetic connections
• Ensuring equitable access to the benefits of science
• Supporting individuals and families with genetic conditions
• Affirming equality
• Managing healthcare costs

Case studies

Victoria Gray (somatic gene editing for sickle cell disease): Gray has sickle cell disease (SCD) caused by a mutation in her HBB genes. SCD can be debilitating and life-shortening; existing treatments only partially address symptoms, and bone marrow transplant — the only cure — is not available to everyone. Gray faced the decision of whether to enrol in the world’s first clinical trial of somatic gene editing for SCD. By February 2023, Gray and 30 other trial participants were symptom-free. Three distinct decisions are in tension: the patient’s decision to enrol; the regulator’s decision on whether the CRISPR-based therapy (“exa-cell”) is safe and effective enough to approve; and the company’s decision on how much to charge for it.

Amanda Baxley (predictive testing and reproductive choice): Baxley is an evangelical Christian opposed to abortion, with a family history of Gerstmann-Straussler-Scheinker disease — a rare, incurable, lethal degenerative genetic brain disorder caused by a prion protein gene variant. She faced two dilemmas: whether to be tested for the disease-causing variant, and whether to undertake IVF with preimplantation genetic diagnosis (PGD) to select unaffected embryos.

Expanded options in fertility medicine (polygenic risk scores): Researchers are building polygenic risk scores (PRS) — disease-risk estimates aggregated from thousands of genetic markers — for a wide range of conditions and traits, from schizophrenia and type 2 diabetes to eye colour and educational attainment. This raises a lawmakers’ dilemma (whether to allow PRS testing, and eventually gene editing, of gametes or embryos for different conditions and traits) and a clinics’ dilemma (whether there are any services a clinic should simply decline to offer).

Self-test

1. Define eugenics as the lecture frames it, and name the range of disciplines it drew on.
2. Describe how eugenic ideology was put into practice in Nazi Germany, using the Goebbels quote and the propaganda poster as evidence.
3. Describe the 1928 New Zealand sterilisation law: who would it have targeted, how much support did it have, and why did it not pass?
4. List, in order, the key developments in clinical genetics from the 1950s through the 1980s.
5. The slide states “OGOD = unusual”. What does it say is common instead, and what does the phrase “we are building the plane, as we’re flying it” convey about clinical genomics?
6. List the six axes along which the nature of a genetic test result can vary.
7. Describe the steps of the CRISPR-Cas9 genome-editing mechanism, in order.
8. The lecture says the impact of genetic test results is “overall less dramatic than anticipated.” What complicates this claim?
9. Distinguish the Angelina Jolie example from the PHAROS Huntington’s disease finding as responses to predictive genetic information.
10. Describe the ethical concern raised by the “warrior gene” reporting and the Havasupai research case.
11. What privacy and geopolitical concern was raised about the BGI prenatal test?
12. List the six ethical commitments the lecture identifies as being in tension in genetics.
13. For the Victoria Gray case study, identify the three different decision-makers and the decision each one faces.
14. Describe Amanda Baxley’s two dilemmas and name the disease at stake.
15. What is a polygenic risk score (PRS), and what dilemma does it create for lawmakers and for fertility clinics?
16. Distinguish somatic from germline gene modification, and describe how the scientific community responded to the arrival of CRISPR-Cas9.
17. Using one of the three case studies, show how at least two of the six ethical commitments in tension apply to it.

Answers

Reveal answers

1. Eugenics is described as “the self-direction of human evolution,” a movement drawing on physiology, biology, genetics, psychology, mental testing, anthropometry, history, geology, archaeology, anthropology, statistics, politics, law, economics, genealogy, sociology and religion, applied through medicine, surgery and psychiatry.
2. Goebbels (1938) said the regime’s goal was “a healthy people” rather than feeding, clothing or aiding individuals; this was backed by bureaucratic record-keeping (ledgers of hereditary status) and propaganda claiming a “hereditarily ill” person cost 50,000 Reichsmark by age 60, depicted as a burden a healthy man had to carry.
3. It would have let a government/medical committee authorise sterilisation of people labelled “feeble minded,” “unfit,” “degenerates,” “imbecile children,” or with “mental defects.” It had broad support among politicians, medics, the judiciary, women’s organisations and academics, and would likely have passed with slightly harder government pushing, but the sterilisation provisions did not pass.
4. 1950s: karyotyping identifies trisomy 21 as the cause of Down syndrome. 1960s: non-directive genetic counselling adopted. 1970s: amniocentesis and CVS developed. 1980s: amniocentesis/CVS increasingly offered as routine prenatal care.
5. The slide says OGOD is unusual and that uncertainty and complexity are common — results vary in risk level, certainty, severity, treatability and onset rather than giving a clean single answer. The “building the plane as we’re flying it” line conveys that clinical practice and guidance for handling these results are being developed at the same time as the testing is already being used on patients. [the slide does not expand the acronym OGOD]
6. High risk ↔ low risk; certain ↔ uncertain; lethal ↔ mild impairment; treatable ↔ not-treatable; child ↔ adult onset; disease ↔ non-disease.
7. (1) Guide RNA plus the Cas9 protein locate a PAM sequence next to a matching genomic sequence. (2) Cas9 cuts the genomic DNA at that site. (3) The cut is repaired by incorporating donor DNA into the genome at the target site, achieving targeted editing.
8. The same kind of genetic information affects different people differently, and most people need help interpreting results — more results generate more complexity, more interpretive work, more counselling, and possibly more follow-up care, even though the average dramatic impact is lower than expected.
9. Jolie chose predictive testing and acted on a high-risk BRCA result with a preventive mastectomy, which she disclosed publicly; the PHAROS study found many people at risk of Huntington’s disease chose not to be tested at all, at lower rates than predicted, for various reasons.
10. The newspaper front page linked a “warrior gene” to violence in a specific ethnic group (Māori), reporting a New Zealand study as controversial, and the Havasupai case involved genetic research conducted on an indigenous tribe becoming “a cautionary tale” — both illustrate risks of genetic research on defined ethnic/indigenous groups. (The slide does not print a gene symbol.)
11. A prenatal test developed with the Chinese military (BGI) collected genetic data from more than 8 million women worldwide using leftover blood samples for population research, and was viewed by the US as a national security threat.
12. Respecting individual autonomy; recognising familial, tribal and genetic connections; ensuring equitable access to the benefits of science; supporting individuals and families with genetic conditions; affirming equality; managing healthcare costs.
13. The patient (Victoria Gray) decides whether to enrol in the world-first somatic gene-editing trial; the regulator decides whether the CRISPR-based therapy (“exa-cell”) is safe and effective enough to approve for sale; the company decides how much to charge for it.
14. Baxley had to decide whether to be tested for the prion protein gene variant causing Gerstmann-Straussler-Scheinker disease (a rare, incurable, lethal degenerative brain disorder), and whether to use IVF with PGD to select embryos unaffected by it.
15. A PRS is a disease-risk estimate built by aggregating thousands of genetic markers, used for conditions/traits ranging from schizophrenia and type 2 diabetes to eye colour and educational attainment; it raises the question for lawmakers of whether to allow PRS testing (and eventually gene editing) of gametes or embryos for such conditions and traits, and for clinics of whether there are services (e.g. selecting cosmetic traits) they should decline to offer.
16. Somatic modification edits body cells, so the change is confined to the treated patient (as in the sickle cell trial); germline modification edits gametes or embryos, so the change is heritable. In response to CRISPR-Cas9, a large group of scientists published a Science article calling for a prudent path forward and an urgent framework for open discourse on genomic engineering and germline gene modification, and international summits on human gene editing were convened (the first in Washington, D.C., 1–3 December 2015; a second summit is shown on the slide, with He Jiankui pictured speaking).
17. For example, in the Victoria Gray case: respecting individual autonomy (her decision to enrol in the trial) sits alongside managing healthcare costs and equitable access (the company’s pricing decision determines who can afford “exa-cell” once approved) — a therapy that works can still be ethically contested if cost puts it out of reach for most patients with the condition.