• Mitochondrial genome: mammoth mtDNA, not elephant mtDNA.

• Germline purity: the resulting animal’s germline carries mammoth DNA end-to-end (no elephant sequence integrated).

• Developmental legitimacy: the embryo runs mammoth developmental programs, with imprinting/epigenetic reprogramming that can actually sustain a viable proboscidean pregnancy.

And you want a moonshot that treats those as requirements, not as “PR definitions.”

Here’s the path I think could plausibly get you there under “near-future tools + unlimited funding,” using what’s already moving in the literature as the slope of the curve.

⸻

The core idea

You do not “clone a mammoth from preserved tissue.” You reconstruct and instantiate a mammoth lineage using a three-part engine:

1. Chromosome-complete mammoth genome definition (sequence + structure + regulatory architecture priors).

2. Whole-genome mammalian rewriting (chromosome-by-chromosome replacement until the cell is mammoth in toto).

3. Germline reboot + artificial gestation (so the organism is born mammoth without elephant cytoplasmic inheritance).

The philosophical move is simple: we stop begging the past to give us intact cells and instead we build the missing substrate ourselves.

⸻

Phase I — Define the mammoth genome as a buildable object (not a fuzzy consensus)

I.1 Pick a “target individual,” then build a pan-genome around it

The purist trap is thinking there’s one “the mammoth genome.” There isn’t; there were populations, clines, drift, introgression. Purism means: pick an individual, reconstruct that mammoth, with optional later diversification.

The enabling step that changes everything: PaleoHi-C / chromatin-contact assembly from ancient tissue. A 52,000-year-old woolly mammoth skin sample retained enough 3D genome structure to assemble 28 chromosome-length scaffolds (and to observe higher-order features like compartments/loops). 

That’s not just “more sequence.” That’s chromosome architecture as data, which is exactly what you need if you ever intend to write a genome rather than align ancient fragments to an elephant reference.

I.2 Close the ugly gaps: repeats, centromeres, telomeres, structural variants

This is where “no elephant DNA infiltration” gets real. Most “reference genomes” are functionally adequate while still being repeat-approximate. For a build, you need explicit decisions about:

• Satellite repeat arrays (centromeres, pericentromeres)

• Subtelomeric repeats

• Segmental duplications

• Large inversions and other SVs

You won’t get those cleanly from short ancient fragments alone. You get them from a synthesis of:

• Contact maps (PaleoHi-C) to lock macrostructure 

• Comparative proboscidean genomics as priors (elephant as constraint, not template)

• Statistical reconstruction with uncertainty tracked explicitly (you don’t pretend—you specify)

The moonshot decision: you don’t wait for perfect recovery. You define a build spec: “This is the most likely chromosome-complete mammoth genome for this individual, with these explicitly modeled uncertainties.” Then you build it and test viability—because viability is an empirical filter that paleogenomics alone can’t give you.

⸻

Phase II — Build “Mammuthus cells” by whole-genome replacement, not patch editing

This is where you reject gradualism in a way that’s actually technical rather than rhetorical.

II.1 Establish a proboscidean cell chassis that can be pushed hard

Elephant iPSCs have now been reported (preprint/news cycle), which matters because it gives you a self-renewing, developmentally flexible substrate you can engineer and select over long campaigns. 

But: we are not ending with elephant DNA. This is scaffolding—your “shipyard.”

II.2 Treat each mammoth chromosome as a synthetic mammalian artificial chromosome

The genome-writing world is moving toward the idea that very large DNA can be built, maintained, and manipulated as artificial chromosomes and inserted/maintained in mammalian cells; recent work explicitly discusses improved large-DNA transfer, human artificial chromosome (HAC) approaches, and mammalian genome “rewriting technologies.” 

Meanwhile, the Synthetic Human Genome effort is explicitly about developing the tools to synthesize long stretches of chromosome and insert them into living cells—i.e., the direction of travel is clear even if the finish line is distant. 

Moonshot interpretation: with unlimited funding, you turn those general technologies into a dedicated Proboscidean Chromosome Foundry. You industrialize the assembly, error correction, and validation of ~28 mammoth chromosomes.

II.3 Replace the elephant nuclear genome chromosome-by-chromosome until none remains

The trick is to avoid a “swap the whole genome at once” fantasy. You do this like a controlled hostile takeover:

1. Introduce one mammoth chromosome (as a stable artificial chromosome).

2. Force loss or silencing of the homologous elephant chromosome (selection systems + cell-cycle tricks + targeted rearrangement tools).

3. Validate viability, karyotype, expression coherence.

4. Repeat, iteratively, until the cell line’s entire nuclear complement is mammoth.

This is exactly the kind of thing genome “rewriting” frameworks are gesturing at: you don’t need whole-genome synthesis in one shot if you can do structured replacement and maintain large DNA stably. 

At the end of Phase II, you have a mammoth-nuclear iPSC line—a living cell that is mammoth in its nuclear DNA.

If you want the purist moment: this is the first time the past stops being inference and becomes a replicating substrate again.

⸻

Phase III — Solve the mitochondrial problem (because purism lives or dies here)

If you tolerate elephant mtDNA, you haven’t done what you asked for. The good news is that mitochondrial genetic tools have advanced sharply: multiple platforms (DdCBE/TALED and related systems) enable targeted mtDNA base editing without guide RNAs and with improving efficiency/specificity. 

The bad news: base editing alone doesn’t obviously give you full arbitrary rewriting (transversions, indels, structural features). So the moonshot isn’t “we can do it today.” The moonshot is:

III.1 Build a “mitochondrial genome replacement” platform, not just editing

With unlimited funding, you run a Manhattan Project for mtDNA replacement:

• Deplete endogenous elephant mtDNA (mito-targeted nucleases have precedent; heteroplasmy shifting is a known strategy class).

• Deliver full-length mammoth mtDNA as a nucleoprotein packaged for mitochondrial import and replication.

• Select for homoplasmy (cells where mammoth mtDNA dominates, then reaches fixation).

• Use base editors to “polish” any residues and to validate causal linkages between mtDNA and phenotype.

The direction is supported by the fact that the mtDNA toolbox is rapidly expanding and being systematized, with explicit discussion of in vivo editing toolkits. 

If you want one place to be “hard because it is hard,” it’s this. But it’s also where concentrated money and talent plausibly compress a decade of incremental work into a single coherent program.

⸻

Phase IV — Germline reboot (so the organism is not merely a cell line)

Even if you have a nuclear-mammoth / mitochondrial-mammoth iPSC, development is not guaranteed. You need the epigenome to be re-set in a way compatible with mammoth embryogenesis. The most credible path is to route through germline specification, because the germline is nature’s own epigenetic reset machinery.

Human germline/PGCLC and epigenetic reprogramming models are advancing quickly, including detailed work on reconstituting aspects of germline epigenetic reprogramming in vitro. 

The sober state-of-the-art: complete oogenesis in primates is still not “solved,” but the trajectory is active and the bottlenecks are increasingly well-characterized. 

Moonshot move: you don’t wait for human IVG to become routine; you build the proboscidean version directly, because you have:

• elephant iPSCs as a training ground 

• embryo models and ex vivo systems expanding the experimentally accessible window of mammalian development 

IV.1 Make mammoth gametes from mammoth iPSCs (no elephant cytoplasm inheritance)

This is the purist masterstroke.

• Differentiate mammoth iPSCs → mammoth PGCLCs → mammoth spermatogonia/oogonia.

• Mature those in gonadal organoids / reconstructed niches.

• Generate mammoth oocytes that carry mammoth mitochondria, and mammoth sperm.

This bypasses the elephant oocyte entirely, which is where mtDNA “infiltration” would otherwise be unavoidable.

⸻

Phase V — Build the embryo, then gestate without borrowing elephant biology as “mother”

If you want “as if on the steppe,” you eventually cannot rely on an elephant uterus as the developmental environment. Not because it changes the genome, but because it changes the maternal-fetal dialogue—immune signaling, placental invasion dynamics, endocrine tempo, nutrient partitioning.

The bridge technology already exists in seed form: ex vivo uterine/implantation systems and extended embryo culture are advancing, including a 2025 ex vivo system that captures key aspects of implantation and early embryogenesis. 

Moonshot move: scale this concept to proboscideans.

V.1 Two-stage gestation architecture

You likely won’t get “zygote to term” ex utero in one leap. So you engineer two stages:

1. Stage A: Implantation and early placentation in a bioengineered uterine interface (the hard immunology + trophoblast invasion problems live here). 

2. Stage B: Mid-to-late gestation in an exo-uterine perfusion system (think: an extremely advanced fetal ICU with a placenta-analog, closed-loop endocrine control, and sterile amniotic environment).

The goal is not sci-fi aesthetics. The goal is to remove elephant-specific maternal biology while still providing the biophysical and hormonal boundary conditions mammoth development expects.

⸻

Phase VI — The birth you’re asking for, and what it means

If all of the above works, the “real deal” birth looks like this in the only way that matters:

• A neonate whose cells, across tissues and germline, validate as mammoth nuclear DNA + mammoth mtDNA.

• A developmental trajectory that matches mammoth growth curves (bone histology, dentition timing, thermoregulation, hair/skin architecture, hemoglobin physiology).

• Later: fertility that produces second-generation mammoths without any elephant genetic input.

At that point the argument ends. Not because critics are silenced, but because biology has been forced to answer.

⸻

Why this is not Shapiro’s gradualism in a trench coat

Shapiro’s gradualism is largely a definition-management strategy under current constraints: “we can get something functionally close; let’s be honest about it.” That’s responsible.

Your demand is different: build the missing substrate and stop negotiating with the constraints as if they were moral truths.

This plan does that in three concrete ways:

1. It insists on whole-genome replacement, not trait editing.

2. It treats mtDNA as non-negotiable and funds the tools to replace it.

3. It treats gestation and germline as engineering domains, not sacred mysteries.

That is the proper “because it is hard” posture: not swagger, but choosing the hardest bottlenecks as primary targets rather than explaining why they’re hard.

⸻

The honest knife-edge

Even with unlimited funding, the plan has genuine cliff risks:

• mtDNA replacement to homoplasmy at scale (hardest)

• correct imprinting / epigenetic reprogramming for a viable proboscidean embryo

• long-duration exo-uterine support for a ~two-year gestation without subtle developmental derailments

But those are not metaphysical impossibilities. They are engineering and developmental biology problems with an obvious attractor: if you can do it for one large mammal, you can generalize.

⸻

The moment

You asked for the heady, insane moment.

It’s not the press conference or the first shaggy coat under studio lights. It’s earlier, quieter: the first time a cell line with an authentic mammoth karyotype and mammoth mitochondria divides cleanly for the thousandth time. Because that’s when the past stops being a museum and becomes a replicator.

And then, later, the real sacrament: a mammoth neonate drawing its first breath—lungs that have never inhaled before, blood with cold-adapted oxygen chemistry, a nervous system lighting up into sensation—and the simplest, most violent scientific fact settles over the room:

the channel was reopened.

Not metaphorically. Not as a simulacrum. Not as an elephant wearing a mammoth costume.

A mammoth.

(http://www.autoadmit.com/thread.php?thread_id=5826678&forum_id=2\u0026mark_id=5310894#49619087)

⸻

Executive decision package

The ask

Authorize a two-year seed commitment of $0.8–$1.2B to (i) lock the mammoth genome build spec to chromosome scale, (ii) stand up the “Chromosome Foundry” and proboscidean cell platform, and (iii) launch the two hardest moonshot workstreams early: mtDNA replacement and exo-uterine gestation.

Why now is technically defensible

• We can already assemble mammoth chromosomes at scale using PaleoHi-C from a 52,000-year-old mammoth sample (28 chromosome-length scaffolds). 

• Elephant iPSCs (a workable proboscidean “cell chassis”) have been reported, enabling sustained, iterative engineering. 

• Embryo implantation/uterine signaling can now be recapitulated ex vivo in model systems—proof of concept for the gestation platform direction (scaling is the challenge). 

• The mtDNA toolbox is moving quickly (high-efficiency, strand-selective mitochondrial base editing exists; full replacement is still the frontier). 

⸻

Phase plan with costs (order-of-magnitude; assumes unlimited funding, parallel execution)

Total program envelope (to first purist birth attempt): $8B–$18B (10–20-year effort; heavy front-loading to de-risk the two hardest gates).

Phase Objective (board-level) Cost range Primary cost drivers

0. Program stand-up (Year 0–1) Build global program: labs, animal/vet infrastructure, compute, governance $250M–$600M Facilities; core teams (400–800 FTE global); biocontainment & QA; legal/reg

I. Mammoth genome “build spec” (Year 0–2) Chromosome-scale nuclear genome + mtDNA; repeat/SV decisions; validation $80M–$250M Ancient DNA work; long-read proxies; compute; QA/replication. (Enabled by PaleoHi-C chromosome assemblies). 

II. Chromosome Foundry + nuclear genome replacement (Year 1–8) Chromosome-by-chromosome replacement until zero elephant nuclear DNA remains in a viable proboscidean iPSC line $2.5B–$6B Large-DNA synthesis/assembly; transfer systems; massive screening/selection; karyotyping; cell QA

III. mtDNA replacement to homoplasmy (Year 1–8) Mammoth mtDNA replacement (not just edits) + proof of stable replication/segregation $1.2B–$3B New tool development; selection systems; single-cell assays; long campaign of heteroplasmy→homoplasmy. (Builds on mito editing toolkit progress). 

IV. Germline reboot (IVG) (Year 2–10) Mammoth gametes from mammoth iPSCs (oocytes must carry mammoth mitochondria) $1.5B–$4B Organotypic culture systems; imprinting/epigenetic reprogramming; reproductive biology scale-up

V. Exo-uterine gestation platform (Year 1–12) Two-stage artificial gestation (implantation/placentation + late-gestation support) $2.0B–$5.0B Bioengineered uterine interface; perfusion/placenta-analog; long-duration sterile systems. (Ex vivo implantation is a directional proof). 

VI. First purist birth attempts + neonatal program (Year 8–15) Attempt pregnancies; neonatal survival; confirm germline purity; F2 generation plan $500M–$1.5B Veterinary/neonatal ICU; longitudinal phenotyping; biosecurity; welfare oversight

Note on “writing DNA” economics: raw synthesis costs are falling (reviewed costs for short synthesis in the ~$0.05–$0.15 per nucleotide range; commercial claims as low as ~$0.15 per bp for certain platforms), but assembly + validation + cellular instantiation dominate cost at mammalian chromosome scale.  A commonly cited estimate (2018) put “writing” a human genome with then-current tech at >$100M—again, that’s writing, not making it live. 

⸻

Probability of success (gated / conditional)

You asked for realism without gradualist defeat. Here it is in the board language: we can buy shots on goal, but two gates are genuinely breakthrough-dependent: mtDNA replacement and full-term ectogenesis/gestation.

Conditional probabilities (today, with aggressive funding)

Gate Success definition P(success) range

G1 Mammoth nuclear genome build spec to chromosome scale (incl. SV/repeats “good enough to build”) 0.80–0.95 

G2 Viable proboscidean iPSC platform robust enough for long campaigns 0.60–0.85 

G3 Full nuclear replacement: stable mammoth-nuclear cell line (no elephant nuclear DNA) 0.15–0.35

G4 mtDNA replacement to mammoth homoplasmy with stable inheritance 0.05–0.20 (tooling is advancing; replacement is the frontier) 

G5 Mammoth gametes (IVG) and viable embryos with correct imprinting 0.05–0.15

G6 Exo-uterine gestation to term for a proboscidean 0.02–0.08 (directional proofs exist; scaling is hard) 

Composite probability (purist mammoth birth)

• Baseline composite: ~0.1%–1%

• Upside (if either G4 or G6 becomes “solved class of problem” early): 2%–5%

• Board-relevant framing: this is a high-variance, high-upside program where early investment is justified by (i) option value, (ii) platform spillovers, and (iii) reputational/scientific leadership if governance is strong.

⸻

Regulatory / policy reality (must be handled upfront)

This program touches:

• U.S. FDA oversight of “intentional genomic alterations” (IGAs) in animals, with updated guidance and an FDA–USDA MOU clarifying roles. 

• Asian elephant constraints: Asian elephants are CITES Appendix I and endangered under U.S. law; any use of elephant biological material/animals must be framed with conservation-first legitimacy and compliant cross-border handling. 

⸻

What the board should focus on (the “7”)

These are the levers that most increase probability of the purist outcome:

1. Stand up a Chromosome Foundry as a standalone platform business

Treat “mammalian chromosome-scale synthesis + transfer + validation” as the keystone capability. Everything else depends on it.

2. Launch the mtDNA Replacement Manhattan Project on Day 1

Base editing exists; replacement to homoplasmy is the hurdle. Fund multiple competing technical approaches in parallel. 

3. Launch Exo-Gestation in parallel with genome work

Don’t wait. The gestation platform is a long pole, even with proof-of-concept ex vivo implantation systems in the literature. 

4. Proboscidean reproductive biology consortium (global, exclusive access)

Secure lawful access to elephant reproductive tissues, veterinary expertise, and ethically governed collaborations (zoos, sanctuaries, range-state institutions).

5. Regulatory architecture and policy coalition

Build a proactive framework with FDA/USDA touchpoints (IGAs), animal welfare standards, and international trade compliance. 

6. Governance that can survive a decade of controversy

Independent animal welfare board, biosafety board, and external ethics review with real veto power. This is reputational risk management and technical risk management.

7. Dual-track “purist” + “platform spillover” metrics

Board needs KPIs that show progress even if the final birth is delayed: chromosome delivery yields, mtDNA heteroplasmy shift rates, embryo viability windows ex vivo, etc.

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Risk factors to watch (and the mitigations a board can mandate)

1. Animal welfare / legitimacy risk (highest reputational consequence)

Mitigation: hard welfare gates; independent oversight; no “hero experiments” that bypass review.

2. Regulatory dead-ends / jurisdictional friction

Mitigation: early FDA engagement (IGA pathway), transparent claims, staged submissions. 

3. Access risk (elephant materials, international constraints, public backlash)

Mitigation: conservation-first partnership model; CITES-compliant protocols; range-state benefit-sharing. 

4. Technical “unknown unknowns” at mtDNA replacement and long-duration ectogenesis

Mitigation: run multiple competing approaches; fund tool-building, not single bets.

5. Biosecurity / dual-use perception

Mitigation: publish governance, auditing, and safety posture; pre-commit to boundaries and transparency.

⸻

Recommended seed funding structure (what you can take to the room)

Authorize $0.8–$1.2B over 24 months, tied to four measurable gates:

• Gate A (6–12 mo): Mammoth genome build spec v1 (chromosome-scale; uncertainty map). 

• Gate B (12–18 mo): Proboscidean iPSC platform reproducible across ≥2 labs. 

• Gate C (18–24 mo): Demonstrate large-chromosome delivery + stable maintenance in proboscidean cells (even if not yet full replacement).

• Gate D (18–24 mo): mtDNA program shows measurable, repeatable heteroplasmy shifting at scale (trajectory toward replacement).

If those gates hit, the board has a rational basis to release the next $3–$5B tranche into Phases II–V.

(http://www.autoadmit.com/thread.php?thread_id=5826678&forum_id=2\u0026mark_id=5310894#49619108)

Yes: I think it’s possible in the physical laws.

No: I don’t think it’s likely on today’s trajectory—even with unlimited money—unless two hard breakthroughs land.

And I do think you can force the conditions under which those breakthroughs are most likely to land.

Here’s me looking you in the eye, in board language:

The honest odds

If you fund it like an F50 wartime program, with parallel paths and a decade+ runway, I’d put the chance of a true purist birth in a single generation at low single digits—~1–5%—but nonzero and meaningfully influenceable. The higher end of that band requires at least one of these becoming a solved class of problem:

1. Mitochondrial genome replacement to stable homoplasmy, and

2. Long-duration ectogenesis (or an equivalent method to avoid elephant maternal biology while maintaining viable development).

If you loosen either of those, the odds jump dramatically. But you explicitly said: don’t loosen them.

What I’m confident about vs what I’m not

Confident (can be engineered with money + talent):

• A chromosome-scale mammoth genome “build spec” good enough to start writing and iterating (PaleoHi-C is a real unlock).

• A proboscidean cell platform that can survive industrial-scale genome engineering.

• Getting to something that is functionally mammoth-like (the Shapiro/Colossal lane) — but that’s not what you asked for.

Not confident (requires breakthroughs, but not magic):

• Full mammalian chromosome-by-chromosome nuclear replacement to a stable, developmentally competent cell line at proboscidean scale.

• mtDNA replacement, not edits: clean, inheritable, stable mammoth mitochondria in the germline.

• Full gestation outside an elephant, at proboscidean duration.

The “if we give everything” answer

If you truly mean “everything”—global talent capture, unconstrained compute, dedicated foundry infrastructure, parallel technical bets, and governance that lets the work proceed without self-immolating in scandal—then yes, it’s worth believing in.

Not because belief changes chemistry. Because belief determines whether you build the kind of institution that can grind down “impossible” problems until they become engineering.

The line I won’t cross

I won’t tell you it’s likely. That’s how moonshots die: by pretending away the hard gates until reality collects interest.

What I will tell you is this: it’s exactly the kind of problem where the first real breakthrough will look like a miracle right up until it’s suddenly reproducible. If you run the program the right way—multiple independent approaches to mtDNA and ectogenesis, ruthless validation, and a tolerance for years of failure—then you maximize the chance that you are the group standing there when the door finally gives.

So: Can we do it?

We might.

And if you’re serious about giving everything, you’re doing the one thing that makes “might” non-trivial: you’re refusing to let the attempt be small.

(http://www.autoadmit.com/thread.php?thread_id=5826678&forum_id=2\u0026mark_id=5310894#49619124)