my_research/politics_of_human_genetic_engg.html

2025-11-07

Politics of human genetic engineering

Disclaimer

• Quick Note
• I don't have a strong opinion on this topic, and am still figuring it out. My weak opinion is that I support a pause on human genetic engg until I figure it out.

What all can we edit?

We can edit capabilities

• We can probably edit (in both upward and downward direction) fluid intelligence (IQ), social intelligence, executive function, working and longterm memory, etc
• How far we can push this, is an open technical question
• We might be able to increase (or decrease) human lifespan, although I don't think it is likely we can fix biological aging and become immortal via gene edits alone.

We can edit psychological traits that are precursors to moral values

• We can probably edit (in both upward and downward direction) respect for authority, empathy, sex drive, ability to experience love or trust, fear and disgust responses, etc
• How far we can push this, is an open technical question
• An important point to note is that moral values are likely not fully decided from birth. Instead, precursors such as empathy and respect for authority may shape how the edited person interacts with others in society as they grow up, and this in turn is what decides their values.

In who can we edit?

• As of 2025, we can definitely edit embryos of our future children, which are grown via IVF.
• We might one day be able to grow these children in artifical wombs also.
• We might one day be able to edit ourselves also, as adults.

Political intermediate states

• Arms race or not?
  • If there is a geopolitical arms race, there is pressure to edit values and capabilities in ways that ensure the children are also able to compete. For instance you will probably want to max out IQ and social intelligence.
  • If there is not an arms race, there is then more slack to edit in whatever values make sense as per one's current ideology. For instance if you are an environmentalist you might to increase empathy for animals in your children, and if you are a muslim you might want to increase respect for authority in your children.
  • I don't know how fast the arms race will be. It seems to depend on how much intelligence increase is possible.
• Are parents free agents?
  • Various political, religious and community leaders will attempt to spread ideology to influence parents' decisions on what values to edit into their children.
  • These leaders might use financial and social incentives (such as collective shaming or collective pride) to coerce parents into editing desired values.
  • In the worst case, this could mean dictators using violence to determine the values of their entire country's future population. They could use violence on parents directly or on political and religious leaders, to ensure only their viewpoint is spread.
  • I don't have any solution to prevent this outcome, besides generic political solutions like toppling over dictatorships and strengthening democracies in today's world.

Political end states

• Permanent monopoly?
  • A small number of powerful humans might edit their children/successors, ensure these people take over the world (by being good at politics and business) and prevent rest of humanity from ever getting access to editing capabilities.
  • To prevent this outcome, researchers can try to open source the tech so it gets copied in multiple countries and work on reducing per-unit cost for the parent. I don't yet know if either of these will be possible to do in practice or not.
  • My guess is this entire scenario is low probability, but I would like to study it more to be more confident.
• Arms race leading to value drift?
  • Assuming a small number of people don't permanently monopolise the tech, we will probably have an uncontrolled arms race. The end state of this arms race is likely a species far superior to humans in terms of intelligence and social intelligence.
  • This species will likely control almost all economic and political power in the world.
  • In the worst case, this species might have mass murdered all non-edited humans. I will bite the bullet and say I am fine with this if (and only if) this superior species also shares some core human values with me.
  • See also: This is loosely analogous to an arms race between digital minds, see also: Zach Davis' poem on this

Open questions

• There are multiple open questions here.
• One major question I consider open is whether core human traits (like empathy) are a capabilities disadvantage or not.
• Example
  • Suppose country A's population edits their population to have increased IQ and increased empathy. Suppose country B's population edits their population to have increased IQ but decreased empathy.
  • (For now let's ignore the question of whether parents made free choices or were coerced.)
  • In the geopolitical arms race between country A and country B, who is at advantage?
  • Which country (if any) is more likely to build to build an overwhelming military advantage to colonise the other country? As of 2025, nuclear-armed countries colonising each other is not likely, but in the limit you can invent sufficiently good weapons and tech that even a nuclear-armed country can be colonised.
    • Yudkowsky supports asking edited humans to build aligned artificial superintelligence. If they build it, then that could enable them to colonise other countries despite the latter having nuclear weapons. (I don't support asking edited humans to build an ASI.)
  • Which country is likely to have more economic power?
  • Which country is likely to be better at persuading people to join it?

Oxytocin

• Some gene clusters are associated with oxytocin levels
• I probably want to read more on experiences of people where oxytocin receptor antagonists were consumed orally / intravenously. Increasing oxytocin via sprays seems more common than decreasing it.
• Lots of anecdotal evidence using oxytocin sprays increases empathy atleast temporarily.
• Decreased oxytocin levels seem to not be studied well. Oxytocin blocking is mostly used clinically for people in pre-term labour, hence most clinical trials also only study this use case.
  • Participants of these trials are blinded, so as per IRB rules, I can't go and just interview them.
  • I or someone else can maybe interview the scientists who ran these trials, they might have anecdotal or unpublished data that is useful.
  • I can read more about animal trials.
  • I or someone else will probably need to conduct new clinical trials, and will probably need IRB approval (assuming trials are done in US).

gpt-5 says, may contain hallucins

Below is a structured literature survey of interventional studies that reduce or block oxytocin (OXT) signaling, including direct oxytocin receptor (OXTR) antagonists and drugs that modulate closely linked upstream/downstream pathways. I separate human clinical trials from work in other species, and note scope limits where evidence is preclinical or mechanistic.

Scope and definitions (what counts as “reducing/blocking oxytocin”)
- Direct OXTR antagonism (peptide and small‑molecule agents).
- Closely coupled pathways with crosstalk to OXT signaling:
  - Vasopressin V1a receptor antagonists (due to OXT–AVP receptor cross‑reactivity and convergent uterotonic/social circuits).
  - Prostaglandin pathway antagonism downstream of OXT in uterus (PGF2α receptor and COX inhibition) as clinically used “indirect OXT pathway” tocolysis.
- Not covered in depth: agents that globally blunt uterine contractility (eg, magnesium sulfate, calcium channel blockers) unless used as comparators.

A. Human clinical trials: direct OXTR antagonists

1) Atosiban (peptide OXTR/V1a antagonist; IV; EU‑approved since 2000)
- Indication: Tocolysis for threatened preterm labor (24–33+6 weeks). Not FDA‑approved in the US, but widely used in Europe. Dosing per EMA EPAR: 6.75 mg IV bolus → 18 mg/h for 3 h → 6 mg/h up to 45 h; may repeat courses. ([ema.europa.eu](https://www.ema.europa.eu/en/medicines/human/EPAR/atosiban-sun?utm_source=openai))
- Major randomized trials:
  - Atosiban vs placebo with rescue (n=501 treated): no difference in time to delivery/therapeutic failure; more women undelivered without alternate tocolytic at 24–48 h and 7 d; signals of worse outcomes when <24–28 w (small subgroup). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10819855/?utm_source=openai))
  - Atosiban vs ritodrine (n=247): similar 48 h and 7 d undelivered rates; fewer maternal adverse effects with atosiban. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10819857/?utm_source=openai))
  - Atosiban vs salbutamol (n=241): similar effectiveness; better tolerability; higher “undelivered without alternative” at 7 d with atosiban. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11574128/?utm_source=openai))
  - Acute intrapartum tocolysis for fetal distress: small RCT showed similar ability to stop contractions but fewer maternal side effects vs hexoprenaline. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15008765/?utm_source=openai))
- Maintenance therapy after an acute episode: large placebo‑controlled RCT (n=513) with subcutaneous infusion pumps found no reduction in preterm birth or improvement in neonatal outcomes; more injection site reactions. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10819856/?utm_source=openai))
- Systematic reviews/meta‑analyses:
  - Cochrane (primary tocolysis): atosiban not superior to placebo/beta‑agonists/CCB for prolongation or neonatal outcomes; fewer maternal side effects; one placebo‑controlled trial signaled more births <28 w and infant deaths—interpret cautiously due to imbalances. ([cochrane.org](https://www.cochrane.org/evidence/CD004452_oxytocin-receptor-antagonists-inhibiting-preterm-labour?utm_source=openai))
  - Cochrane (maintenance therapy): insufficient evidence of benefit. ([cochrane.org](https://www.cochrane.org/CD005938/PREG_oxytocin-antagonists-for-suppressing-preterm-birth-after-an-episode-of-preterm-labour?utm_source=openai))

2) Barusiban (long‑acting peptide OXTR antagonist; IV)
- Threatened preterm labor (34–35+6 w): randomized, double‑blind, dose‑ranging, placebo‑controlled trial (n=163) found no reduction in contractions or delivery <48 h; safety acceptable; development discontinued. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/19306963/?utm_source=openai))

3) Retosiban (GSK221149A; small‑molecule, selective OXTR antagonist; IV infusion)
- Phase 2 proof‑of‑concept RCT (women 30–35+6 w sPTL): increased time to delivery vs placebo by ~8 days; lower preterm birth proportion; maternal/fetal safety similar (pilot size). ([ore.exeter.ac.uk](https://ore.exeter.ac.uk/repository/handle/10871/17335?utm_source=openai))
- Phase 3 program announced 2015 (retosiban vs atosiban), later terminated early for poor enrolment; infant follow‑up (ARIOS) suggested comparable safety but trials underpowered. ([gsk.com](https://www.gsk.com/en-gb/media/press-releases/gsk-announces-start-of-phase-iii-programme-to-evaluate-retosiban-for-spontaneous-preterm-labour/?utm_source=openai))
- Phase 1 PK/safety in healthy women (Japanese/white): similar exposure; regimen used for sPTL studies. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/28419732/?utm_source=openai))
- Mechanistic human myometrium studies support potent, reversible antagonism; distinct signaling profile vs epelsiban/atosiban. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31907536/?utm_source=openai))

4) Nolasiban (OBE001; oral small‑molecule OXTR antagonist) for IVF embryo transfer
- Pooled IPD meta‑analysis of three randomized trials: single 900 mg dose 4 h pre‑ET increased ongoing pregnancy ~5% absolute (95% CI 0.5–9.5); well tolerated. ([academic.oup.com](https://academic.oup.com/humrep/article/36/4/1007/6127349?utm_source=openai))
- Large Phase 3 (IMPLANT4; n≈807) was negative for the primary endpoint (ongoing pregnancy at 10 weeks); program in IVF halted in 2019. ([pharmatimes.com](https://pharmatimes.com/news/obseva_ditches_ivf_trial_after_disappointing_late-stage_results_1316403/?utm_source=openai))

5) Epelsiban (GSK557296; selective OXTR antagonist) for premature ejaculation (PE)
- Phase 2 RCT (N=77): well tolerated but no clinically/statistically significant change in intravaginal ejaculatory latency time (IELT) vs placebo. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/23937679/))

6) Cligosiban (IX‑01; OXTR antagonist) for PE
- Proof‑of‑concept Phase 2 (PEPIX): on‑demand dosing prolonged IELT and improved patient‑reported outcomes. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31351659/?utm_source=openai))
- Phase 2b (PEDRIX): three fixed dose levels failed to separate from placebo; program discontinued. ([academic.oup.com](https://academic.oup.com/jsm/article/16/8/1188/6980596?utm_source=openai))

7) L‑368,899 (non‑peptide OXTR antagonist)
- Early human work reported Phase 1 completion and blockade of OT‑stimulated postpartum uterine activity; widely used later as a CNS‑penetrant antagonist in animal/human experimental medicine, but no completed efficacy trials in a licensed indication. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/8714024/?utm_source=openai))

B. Human clinical trials: upstream/downstream pathway antagonists

1) Vasopressin V1a receptor antagonists (cross‑talk with OXT pathways)
- Relcovaptan (SR49059; oral V1a antagonist) for primary dysmenorrhea: double‑blind, randomized, placebo‑controlled, cross‑over trial showed dose‑related pain reduction; also inhibits AVP‑induced uterine contractions in vivo; no clear effect on oxytocin‑induced contractions at studied doses. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10826575/?utm_source=openai))
- SRX246 (brain‑penetrant V1a antagonist): randomized trials show safety/tolerability and signal on anxiety‑potentiated startle in healthy volunteers; exploratory Phase 2 in Huntington’s disease (irritability/aggression) indicated safety and behavioral signals; a PTSD crossover study was terminated early (recruitment/logistics), with protocol published. These target AVP but are pertinent to the OXT–AVP social/affective axis. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33970290/?utm_source=openai))

2) Prostaglandin pathway antagonists (uterine “downstream” of OXT)
- Ebopiprant (OBE022; oral PGF2α receptor antagonist) in spontaneous preterm labor:
  - Phase 2a PROLONG (randomized, double‑blind, placebo‑controlled) used as add‑on to standard atosiban infusion for 48 h (N=113). Delivery within 48 h occurred in 12.5% with ebopiprant vs 21.8% with placebo (adj OR 0.52; 90% CI 0.22–1.23), suggesting possible benefit, especially in singletons; safety similar. Program licensed to Organon to continue development; peer‑reviewed results appeared in 2024. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/40782442/?utm_source=openai))
- COX inhibitors (eg, indomethacin) reduce prostaglandins downstream of OXT; RCTs and Cochrane reviews show pregnancy prolongation vs some comparators but with important fetal safety concerns (ductus arteriosus constriction, oligohydramnios) and limited evidence for improved neonatal outcomes; contemporary obstetric use is cautious and time‑limited. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15846626/?utm_source=openai))

C. Other species (controlled in vivo studies; many are “experimental” rather than clinical)

Nonhuman primates
- L‑368,899 IV reaches CSF and limbic regions in rhesus macaques and reduces maternal interest and sexual behavior—first direct evidence that endogenous OT supports primate maternal/sexual behaviors. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/17583705/?utm_source=openai))
- Oral OXTR antagonist (L‑368,899) reduced pair‑bonding proximity/huddling in marmosets during early cohabitation (partner preference dynamics). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/20025881/?utm_source=openai))

Rodents and fish (selected translational examples)
- Prairie vole: OXTR antagonism (L‑368,899) increased depression‑relevant behaviors and heart rate, paralleling effects of social isolation. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/35240436/?utm_source=openai))
- Zebrafish: L‑368,899 selectively inhibits zebrafish OXT receptors and reduces social preference; other experiments show complex interactions with NMDA antagonist‑induced social deficits. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32214126/?utm_source=openai))

Large animals and lactation
- Dairy cows: Atosiban inhibits milk ejection; pharmacokinetics and intramammary pressure studies show robust blockade of oxytocin‑induced letdown. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10191468/?utm_source=openai))
- Lactating rats: central OXT actions on milk ejection are blocked by intracerebroventricular peptide OTA; systemic peptide OTA (including atosiban analogs) acts peripherally and does not enter brain to block central OXT‑neuronal burst firing. ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4982133/?utm_source=openai))

D. What the trials collectively show (human)
- Obstetric tocolysis: Direct OXTR antagonism safely suppresses uterine activity with fewer maternal side effects than beta‑agonists, but superiority for prolongation or neonatal outcomes has not been demonstrated; one placebo‑controlled trial signaled possible harm in extremely preterm gestations (<28 w), warranting caution. Retosiban had encouraging Phase 2 data, but Phase 3 enrollment problems and no definitive efficacy signal to date; barusiban was negative. ([cochrane.org](https://www.cochrane.org/evidence/CD004452_oxytocin-receptor-antagonists-inhibiting-preterm-labour?utm_source=openai))
- Reproductive medicine (IVF): Nolasiban had supportive pooled Phase 2 findings but failed in Phase 3 and the IVF program was discontinued. ([academic.oup.com](https://academic.oup.com/humrep/article/36/4/1007/6127349?utm_source=openai))
- Sexual medicine (PE): Mixed results—cligosiban showed early proof‑of‑concept but failed in Phase 2b; epelsiban Phase 2 was negative. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31351659/?utm_source=openai))
- Indirect “OXT pathway” tocolysis: selective PGF2α antagonism (ebopiprant) is a promising downstream strategy with early evidence (as add‑on to atosiban) and a cleaner fetal safety rationale than nonselective COX inhibitors; larger trials are warranted. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/40782442/?utm_source=openai))
- CNS/behavioral: No approved OXTR antagonists for psychiatric indications; translational work increasingly targets AVP V1a (eg, SRX246) with supportive experimental findings for anxiety/aggression circuits, reflecting OXT–AVP system interplay. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33970290/?utm_source=openai))

E. Safety considerations
- Maternal: Atosiban has a favorable side‑effect profile vs beta‑agonists; injection‑site reactions are common with SC maintenance. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11574128/?utm_source=openai))
- Fetus/neonate: Overall neonatal outcomes with OXTR antagonists have not improved vs comparators; signal for harm at very early gestations in one atosiban trial requires caution. Ebopiprant early data do not show added safety risk; indomethacin and other COX inhibitors carry recognized fetal risks if used beyond ~32 w or for prolonged courses. ([cochrane.org](https://www.cochrane.org/evidence/CD004452_oxytocin-receptor-antagonists-inhibiting-preterm-labour?utm_source=openai))
- Lactation: OXTR blockade can inhibit milk ejection in large animals; peptide OTAs do not appear to block central OXT neurons when given systemically in rodents, but practical implications for human postpartum lactation with obstetric dosing are limited/uncertain. ([cambridge.org](https://www.cambridge.org/core/journals/journal-of-dairy-research/article/atosiban-an-oxytocin-receptor-blocking-agent-pharmacokinetics-and-inhibition-of-milk-ejection-in-dairy-cows/299F7459FD33D7C66004EA051B174AC2?utm_source=openai))

F. Mechanistic notes and upstream control
- OXTR expression is modulated by sex steroids; estradiol tends to up‑regulate and progesterone can counter‑regulate OXTR in human myometrial models, though in vivo correlations are complex. These findings explain why progesterone is used for preterm birth prevention via multiple mechanisms, but this is not a specific OXT‑targeting intervention in clinical trials. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/8589505/?utm_source=openai))

Key references (selection)
- Cochrane reviews on OXTR antagonists (primary and maintenance tocolysis). ([cochrane.org](https://www.cochrane.org/evidence/CD004452_oxytocin-receptor-antagonists-inhibiting-preterm-labour?utm_source=openai))
- Atosiban pivotal trials and regulatory summaries. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10819855/?utm_source=openai))
- Barusiban RCT. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/19306963/?utm_source=openai))
- Retosiban Phase 2 POC; Phase 3 initiation and follow‑up; pharmacology. ([ore.exeter.ac.uk](https://ore.exeter.ac.uk/repository/handle/10871/17335?utm_source=openai))
- Nolasiban meta‑analysis and Phase 3 failure. ([academic.oup.com](https://academic.oup.com/humrep/article/36/4/1007/6127349?utm_source=openai))
- Epelsiban and cligosiban PE trials. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/23937679/))
- Ebopiprant PROLONG study (add‑on to atosiban). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/40782442/?utm_source=openai))
- COX inhibitors for tocolysis (Cochrane/RCT). ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15846626/?utm_source=openai))
- Nonhuman primate OXTR blockade (L‑368,899) and lactation models. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/17583705/?utm_source=openai))

Open questions and gaps
- Definitive neonatal benefit from direct OXTR antagonism in sPTL remains unproven; larger, well‑powered trials in clearly defined gestational strata (and with modern neonatal care endpoints) are needed. ([cochrane.org](https://www.cochrane.org/evidence/CD004452_oxytocin-receptor-antagonists-inhibiting-preterm-labour?utm_source=openai))
- For implantation support (IVF), negative Phase 3 results with nolasiban temper enthusiasm despite earlier signals; any future use would need clearer pharmacology/PK‑PD rationale (eg, dosing/timing). ([pharmatimes.com](https://pharmatimes.com/news/obseva_ditches_ivf_trial_after_disappointing_late-stage_results_1316403/?utm_source=openai))
- Downstream selective PGF2α antagonism (ebopiprant) is currently the most active development path; replication in larger studies and without mandatory atosiban background would clarify effect size and practical use. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/40782442/?utm_source=openai))
- CNS indications: no completed positive efficacy trials with OXTR antagonists; AVP V1a antagonists (SRX246) show translational signals for anxiety/aggression but need confirmatory clinical data. ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33970290/?utm_source=openai))

Would you like this turned into a compact spreadsheet (agent, target, trial phase/ID, population, primary endpoint, topline result, citation), or exported as BibTeX?

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