Advanced Therapies 2020–2025: A Scientific and Business Canon for Repeatable Breakthroughs

Between 2020 and 2025, advanced therapies ceased to be a collection of extraordinary case reports and became a system: a way of designing, manufacturing, governing, funding and delivering medicines that can credibly promise single administration cures or programmable, repeatable biology. This article is written for scientists, executives and investors who need both layers, the mechanism and the model, because in this field they are inseparable. The article draws on the public record of approvals and guidance, the mechanistic literature, the manufacturing and enforcement archives, and the capital cycles that rewarded certainty. The argument is simple: in advanced therapies, delivery is the product itself; analytics are clinical; safety is a mechanism; regulation is supervised learning; capacity is a financial instrument; and value accrues to those who operate as if all five statements are true at once.

1) Foundations: from plausibility to programmability

Two revolutions set the baseline for the 2020s. First, genome editing became programmable. The 2012 description of an RNA guided nuclease turned genetic intervention from a bespoke protein engineering exercise dominated by highly complex Zinc Finger Nucleases designs (ZFNs) into a much simpler guide sequence design problem, collapsing iteration cycles from years to weeks ^[1]. Within two years, practice had converged on a general workflow that made ex vivo editing of hematopoietic stem and progenitor cells (HSPCs) feasible at clinical scales and, critically, characterizable before infusion ^[2].

Second, by 2017 oligonucleotide chemistry and delivery matured into drug grade platforms. Phosphorothioate linkages, 2′ O substitutions and conformationally constrained sugars hardened antisense and small interfering RNA (siRNA) against nucleases and innate sensors; lipid nanoparticles (LNPs) became the modular vehicle that delivers nucleic acids into hepatocytes and beyond ^[3][4]. These achievements generated a platform logic. Once the vehicle is industrialized, the sequence becomes a programmable variable with a stable cost curve.

Clinical proofs followed, with operational demands attached. During 2016 to the early 2020s, CAR T demonstrated curative potential in B cell malignancies and forced oncology to institutionalize new behaviors including graded, protocolized management of cytokine release and neurotoxicity; potency assays linked to biology; and supply chains prepared for living drugs ^[5]. Adeno associated virus (AAV) showed that durable expression in non dividing cells was more than a promise, and then demanded that the field learn the chemistry and immunology of its limits: payload caps, serostatus, platform dependent impurities and dose immune interactions ^[6]. LNP mRNA moved beyond vaccines towards transient protein replacement and in vivo editing reagents, provided endosomal escape and stability were engineered rather than assumed ^[7][8][9].

By 2020, "can we?" was no longer the gating question. The decade's second half would be decided by how delivery, analytics, safety, governance and capacity turned plausibility into repeatability.

2) Modalities that actually scale: mechanisms, use cases and constraints

The lexicon of advanced therapies is often spoken in names including AAV, LNP mRNA, ASO/siRNA, lentiviral HSC, CAR T, CAR NK, … but the grammar that makes those words intelligible to clinicians, regulators and investors is mechanistic. A modality is not a mere label but rather a linked set of choices about how a payload will enter a body, which cells it will reach, how long it will persist, and what the immune system and manufacturing system will make of the attempt. This section lays out that grammar.

AAV (in vivo gene transfer)

Adeno associated virus (AAV) in vivo gene transfer remains the purest expression of one time molecular medicine. Mechanistically, recombinant AAV delivers a DNA cassette that can persist in non dividing cells for years, producing durable protein expression after a single administration. That promise brings three design constraints to the foreground:

Dosing Strategy: Upon successful design, dosing then becomes the calculus that ties these axes together. AAV dose is typically expressed in vector genomes per kilogram (vg/kg). Improvements in on target transduction via capsid engineering or expression cassettes with tissue appropriate promoters combine multiplicatively with local delivery to reduce systemic exposure. Conversely, poor capsid choice or a cassette that burdens cells can push doses into ranges where complement activation becomes more probable. The business ramification is clear: capsid engineering that genuinely reduces hepatocyte transduction at equal efficacy is a Cost of Goods Sold (COGS) and label changing event, because it moves a program from managing high dose risk with aggressive monitoring to managing lower dose risk with routine lab schedules.

Ex vivo lentiviral HSC gene addition

For the non-scientific reader we should first clarify an important distinction between AAVs and lentiviruses: lentiviral vectors integrate permanently into the host genome and whereas during the last decades we have been able to engineer multiple different modalities, they are generally characterized by random integrations that increase oncogenic risk. However, integrating vectors address a different biological niche: dividing lineages in which durability matters. In hemoglobinopathies, autologous HSPCs are collected by apheresis, transduced ex vivo with a lentiviral vector encoding a therapeutic cassette (e.g., a β globin with anti sickling properties), and reinfused after myeloablative conditioning to make room for engraftment. Integration near transcriptionally active chromatin confers long term expression across erythroid progeny. Modern vectors use self inactivating (SIN) Long Terminal Repeats (LTRs) to reduce promoter activity in the long terminal repeats, lineage appropriate internal promoters to restrict ectopic activation risk, and insulator elements to blunt enhancer spillover. Vector copy number per cell, integration site distribution, and functional potency (e.g., hemoglobin A restoration in ex vivo differentiation models) become release criteria, rather than research assays.

The safety advantage flows directly from that ex vivo control. Because the product can be tested before infusion, oncogenic risk flags like clonal overgrowth or karyotypic abnormalities can be detected and excluded. Integration site analysis by ligation mediated PCR or NGS allows clonal tracking in vivo, turning long term follow up (LTFU; the extended monitoring of patients or clinical trial participants after treatment, crucial for assessing the ongoing effects, safety, and efficacy of intervention) into a scientific instrument rather than a bureaucratic burden. Therefore, the major work moves to CMC: closed system processing, sterile connections, validated cryopreservation, thaw and infusion procedures, and potency assays that correlate with clinical endpoints. Economically, the quasi fixed per patient costs (apheresis, conditioning, site readiness) mean that as programs scale, the per dose COGS improvement rests as much on suite utilization and scheduling as it does on vector yield.

Engineered immune cells (CAR T, allogeneic T, NK)

Engineered cell therapies are living drugs whose "delivery" is a choreography of receptor design, manufacturing, and clinical service. CAR T constructs pair an extracellular single chain variable fragment (scFv) with intracellular signaling domains; swapping CD28, the prototypical costimulatory domain that drives strong initial T-cell activation and glycolytic metabolism, for 4 1BB costimulation which promotes oxidative metabolism and memory differentiation, changes mitochondrial biogenesis, expansion kinetics and persistence, which is why two products against the same antigen can have different clinical profiles. In early programs, efficacy arrived with novel toxicities: cytokine release syndrome (IL 6, IFN γ and others) and neurotoxicity. The field's standardization—grading scales, early tocilizumab for CRS, ICU care pathways for neurotoxicity—transformed an experimental surge into a manageable clinical phase. The FDA's 2025 elimination of REMS for autologous CAR T products reflects confidence that boxed warnings, labeling and pharmacovigilance can preserve safety in routine use [17,18].

Allogeneic strategies and NK platforms pursue access and cost by decoupling manufacturing from individual patients. Allogeneic T cells typically require genetic editing to reduce GVHD risk and host rejection(e.g., TRAC disruption to eliminate endogenous TCR and B2M to remove MHC I). NK cells, which do not mediate GVHD like mature T cells, offer attractive safety profiles and simpler logistics, though persistence often lags and repeated dose strategies are needed. The business question for allogeneic products is not simply whether they can be produced cheaply; but instead whether they can sustain persistence safely enough to generate outcomes comparable to autologous therapies while unlocking different distribution models.

RNA therapeutics (ASO/siRNA, LNP mRNA)

Oligonucleotide therapeutics are the most chemistry driven of all advanced therapy modalities. Antisense oligos can be designed to recruit RNase H, the endogenous nuclease that degrades RNA in RNA–DNA hybrids, to eliminate target transcripts or to modulate splicing/translation sterically; siRNAs engage the cell's RNA silencing machinery (RNA induced silencing complex; RISC) for target cleavage. The medicinal chemistry changes as 2′ O substitutions, constrained sugars, and backbone stereochemistry, tunes affinity, stability and innate immune recognition [17]. Conjugation with N acetylgalactosamine (GalNAc) converts pharmacokinetics into a receptor mediated process via the asialoglycoprotein receptor on hepatocytes, enabling low dose, infrequent subcutaneous administration and a clear clinical/COGS profile. In the CNS, intrathecal administration remains the practical route; distribution is governed by CSF flow and tissue penetration rather than systemic circulation.

LNP mRNA adds the physics of colloids to the pharmacology. The ionizable lipid must be neutral in circulation and protonatable in the endosome to promote escape; helper phospholipids and cholesterol set membrane fusion and phase behavior; PEG lipids tune colloidal stability, opsonization and biodistribution. Rational tweaks like spiking in biodegradable tertiary amine polymers can dramatically increase endosomal escape without proportionately increasing innate cytokine release, a route to potency that does not tax tolerability ^[7]. Stability is the gatekeeper for access: the amount of water in the particle core and the details of mRNA–lipid interactions determine whether a formulation can be lyophilized without losing in vivo potency. That decision line is not just a formulation problem; it is a market problem: a thermostable product can reach pharmacies without a dedicated cold chain ^[8][9].

3) Approvals and trial energy: what the system now rewards

The approvals that marked 2020–2025 were milestones and mirrors. TECARTUS (brexucabtagene autoleucel) in 2020 showed that the FDA would license a living drug with explicit boxed warnings and long term follow up, if clinical benefit justified it and facility readiness could be demonstrated ^[18]. ABECMA (2021) and CARVYKTI (2022) then made BCMA CAR T a class with curative intent in myeloma ^[19][20]. The economic message was as significant as the clinical one: institutions that could satisfy REMS era requirements and manage toxicity safely were rewarded with access and volume; those that could not were gated out until 2025, when REMS was eliminated.

HEMGENIX (etranacogene dezaparvovec) flipped the switch for AAV in hemophilia B (U.S., 2022) and entered the EU under conditional authorization in 2023 ^[21][22]. Both decisions formalized the lifecycle bargain: early access when benefit is high and unmet need is clear, but only if sponsors commit to post authorization evidence and long term safety monitoring. In practical terms, these labels catalyzed payer conversations not about whether gene therapy exists but about how outcomes will be measured and how risks will be shared.

The approvals of ex vivo gene edited HSPCs (CASGEVY) and lentiviral HSC (LYFGENIA) in late 2023 in hemoglobinopathies did something else: they made clear that genome edited autografts can meet safety and efficacy bars when CMC is rigorous and LTFU is serious ^[23][24]. From an operating perspective, these approvals knighted a set of analytics—VCN, integration site mapping, potency assays—as clinical documents rather than research artifacts, and they validated operational strategies (e.g., multi center site qualification and patient logistics) that others can now emulate.

Guidance documents matured in the background, turning tacit knowledge into explicit rules. FDA's 2020 LTFU guidance made multi year safety surveillance a standard for gene therapies ^[25]. Its 2024 CAR T guidance elevated potency, comparability and safety into gatekeepers for development plans ^[26]. The EMA's ATMP trial guideline harmonized clinical and quality requirements across member states, enabling multinational sponsors to plan trials against a shared template ^[27]. Approvals and guidance are now halves of a single system: licensure pulls the field forward; guidance prevents backsliding.

The registry tells you where the energy went. AAV moved towards organ targeted programs and refined routes (ophthalmology; selected CNS approaches including intrathecal/cisterna magna), where exposure is localized and dose can be titrated. CAR T diversified into autoimmunity with trials designed to "reset" B cell repertoire, and into solid tumors with bispecific/armored constructs that attempt to overcome antigen heterogeneity and immune suppression. mRNA moved beyond vaccines into systemic EV mRNA delivery for Duchenne and personalized neoantigen vaccinations; an mRNA encoded CD19/CD3 engager in autoimmunity explored a transient expression format for bispecific logic ^[28–34]. The shared characteristics of these trials, declared LTFU, explicit immunomonitoring, and upstream CMC aligned with comparability, mirror the rules approvals wrote.

4) Safety as mechanism: how the field learned to act fast

The true inflection point for a new class of medicines is the moment the field must confront a harm it had not fully anticipated and decide, together, whether it can learn fast enough to preserve trust. Between 2020 and 2025, advanced therapies experienced that collective test. Single administration gene therapies encountered rare but severe hepatic events after systemic dosing; the immune logic of complement activation, long suspected, became mechanistically explicit; and a high profile muscular dystrophy program triggered regulator actions that radiated across an entire serotype platform. At the same time, the less regulated margins of regenerative medicine—exosome products, perinatal tissue injectables, clinic marketed "stem cell" offerings—drew a fusillade of warning letters as the U.S. Food and Drug Administration (FDA) sought to redraw the boundary between innovation and unlawful risk. This section briefly discusses some notable case studies.

The Elevidys cascade: a chronology of scrutiny, action, and divergence

The general became specific in the summer of 2025. The product in question—delandistrogene moxeparvovec, marketed as Elevidys—had never enjoyed an easy consensus. Its accelerated approval in 2023 rested on a surrogate endpoint (micro dystrophin expression) that divided FDA reviewers and inspired an advisory committee debate that was as much about epistemology—what counts as evidence—as it was about data. The Summary Basis for Regulatory Action reads like a record of tension: between clinical urgency in a lethal pediatric disease and an approval standard that insists that a biomarker must be "reasonably likely" to predict clinical benefit. When the agency granted accelerated approval, it did so with eyes open to the possibility that post approval evidence could alter the calculus.

Two years later, in June 2025, the FDA publicly announced that it was investigating two reported deaths from acute liver failure in non ambulatory Duchenne muscular dystrophy patients who had received Elevidys, and that, in the agency's view at that moment, the deaths appeared related to treatment ^[35]. In the space of a single page, the communication reframed both the product and the platform it stood on. It pointed to the existing label language about serious liver injury and signaled that those words might not be enough; it told clinicians to monitor transaminases and clinical status closely; it warned the public that the agency was prepared to take further regulatory action. Executives read it with the cold attention such notices demand: this was not a reminder; it was a preface.

The preface became action on July 18, when the FDA announced that it had placed Sarepta's investigational trials using the same AAVrh74 serotype on clinical hold, revoked the company's platform designation for AAVrh74, and requested that the firm voluntarily suspend distribution of Elevidys while the investigations proceeded ^[36]. The press release did not bury the lede. It quoted agency leadership on the priority of patient safety and, unusually, recorded the fact that the company had declined the request to suspend ambulatory patient shipments at that time. In an industry where polite euphemism is the language of disagreement, this was extraordinary candor. The signal to the market was plain: the agency regarded the events not as a program specific oddity but as a class relevant concern within a serotype platform. Within days, on July 22, the company paused U.S. shipments. And within a week, when evidence emerged that an eight year old ambulatory patient's death was unrelated to the therapy, the agency publicly recommended lifting the voluntary hold for ambulatory patients even as it left non ambulatory shipments paused pending further work ^[35-37].

Across the Atlantic, the European Medicines Agency followed its own logic to a severe conclusion. On July 24, 2025, its Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion recommending refusal of marketing authorization for Elevidys, citing the failure to demonstrate clinically meaningful benefit on movement after twelve months and the persistence of safety concerns ^[38]. Where the FDA had accepted a surrogate once and was now testing the safety perimeter, the EMA concluded that benefit had not been shown and that the risk–benefit profile did not justify approval. The combined effect of these actions was to strain a company, divide a community and clarify a principle: when a platform is treated as a platform then events in one program have consequences in others.

It is worth pausing on what the Elevidys chronology actually accomplished. It made explicit what had been implicit: the agency will not hesitate to intervene across a platform when it perceives a class level signal, and it will calibrate those interventions as evidence evolves. It told sponsors that the privilege of a platform designation is matched by the obligation to treat adverse events as potentially generalizable until proven otherwise. It told clinicians and patients that the agency will display its reasoning in public, in real time, and will adjust as facts change. And it taught investors how quickly a single program crisis can metastasize into a franchise level question.

Exosomes and the policing of the regenerative medicine border

While AAV and cell editing programs occupy the regulated center of advanced therapeutics, a different safety drama unfolded along the border where innovation becomes a business before it becomes a medicine. In December 2019 the FDA issued a public safety notification warning that so called exosome products marketed for the treatment of diseases were unapproved and could be associated with serious adverse events; the notice emphasized that such products are biological drugs that require formal approval and that the agency was aware of patient harms ^[39]. Over the next several years, that warning matured into an enforcement line. Between 2024 and 2025 the agency issued a series of warning letters to firms marketing umbilical cord derived "exosomes" and tissue derived injectables for a menagerie of indications—autoimmune disease, neurodegeneration, orthopedic repair—without approved applications or lawful exemptions.

The letters have a pattern. They begin by noting the intended uses—statements on websites and social media that establish objective intent to treat disease—and then explain why the products are not eligible for the narrow human cell and tissue based product (HCT/P) exemptions: the processing exceeds minimal manipulation; the proposed use is not homologous; the products are administered systemically and thus are subject to drug and biologic regulation. They then catalogue manufacturing deficiencies that, in any GMP regulated plant, would halt production: inadequate environmental monitoring for aseptic processing, lack of validated sterility testing, unsupported expiration dating, incomplete donor eligibility records. And they close by demanding corrective action, often within fifteen working days, while referencing the earlier safety notification and, in some cases, observing that the firms had continued to make claims after prior agency contact ^[40–46]. The enforcement was a bid to collapse the space where the words "stem cell" and "exosome" act as marketing gloss over what are, in regulatory fact, unapproved drugs.

The implication is that high velocity learning, much needed in drug discovery and development, is only possible when mechanisms are named, and when regulators treat approvals as the beginning of supervised learning rather than the end of review. The field's work is to be ready to use both facts and flex.

5) Lifecycle governance: approvals are the beginning

Lifecycle governance is the idea that a durable therapy's evidence must accumulate in use as much as in trials. FDA's 2020 LTFU guidance turned that idea into rules: five to fifteen years of follow up for integrating vectors and other products where biology demands it; structured safety reporting; and preference for registry or observational designs that can capture late effects reliably at scale ^[25]. EMA's conditional marketing authorization process wrote the same bargain into EU law: access today in exchange for evidence tomorrow, documented as post authorization obligations ^[22]. These frameworks do not slow progress; they keep promises.

In cell therapy, FDA's 2024 guidance matured field practice into expectations: potency assays that correlate with mechanism and outcome; comparability demonstration for process, site or scale changes; and standardized safety monitoring for CRS/ICANS ^[26]. In June 2025, the agency eliminated REMS for autologous CAR T therapies, concluding that labeling and pharmacovigilance were sufficient to assure safe use ^[15]. The KYMRIAH approval letter made the logic explicit: monitoring requirements were clarified in labeling, and site certification requirements were removed from REMS ^[16].

Coverage will need to catch up. Medicare's NCD 110.24 historically tied coverage to REMS enrollment. As REMS disappears, contractors must update coverage articles and claims systems to avoid denials based on requirements that no longer exist ^[47]. Sponsors can accelerate alignment by publishing site readiness criteria and post marketing safety data that give payers confidence to expand access beyond flagship centers.

Governance, in short, is not, as many would believe, a brake. Instead, it became the scaffolding that allowed the field to move quickly when it needed to and to relax barriers when evidence allowed.

6) Capacity and comparability: where value was made (or lost)

Manufacturing and supply chains were the decisive differentiators of this period. In 2020, Lonza's drug substance collaboration with Moderna and Catalent's dedicated high speed fill–finish arrangement transformed scarcity into annuity like revenue streams for CDMOs ^[48][49]. Thermo Fisher's earlier consolidation of Brammer Bio looked prescient as viral vector demand surged; Samsung Biologics' reported record $1.41B contract (2025) and WuXi Biologics' multi site expansions cemented investor belief that pricing power accrues to validated, flexible, end to end capacity ^[50][53][52].

On the other side of the ledger, the Emergent/Baltimore episode (2021), in where tens of millions of vaccine doses destroyed due to contamination, provided a stark illustration of single site risk ^[54]. Sponsors have since rewritten operating plans accordingly: redundancy (primary and backup slots for drug substance and fill–finish), change control language in contracts that pre agree comparability evidence, and funded options on lyophilization or specialty fill lines. The most sophisticated added minority stakes in suppliers, embedded staff on suite floors, or negotiated right of first refusal for critical campaigns. The market started to price those choices as real assets rather than soft assurances.

Comparability and analytics, once considered back office, became front page drivers of enterprise value. The public learned the biology: capsid PTMs and P:I ratios differ by platform and map to potency ^[12]. Regulators made the policy: show that a change in platform or scale does not change the product in ways that matter. Sponsors made the practice: multi attribute mass spec panels, high fidelity genome integrity assays, orthogonal vg and infectivity measures, and bridging studies designed before a transfer, not after a delay. FDA's 2023 untitled letter to Novartis (Kymriah, Morris Plains) made quality failure tangible: recurrent particulate contamination, mold recoveries in ISO classified spaces, inadequate validation of reprocessing and gaps in laboratory control ^[55]. No investor who read it thinks of quality as a regulatory chore anymore; they think of it as a clinical variable with an enterprise value multiplier.

Finally, raw materials and process adjacent constraints such as plasmid DNA, lipids for LNP, sterile single use assemblies, proved their ability to slow programs. Sponsors that locked multi year supply agreements or verticalized selectively (e.g., in house plasmid) moved faster and with fewer surprises than those that treated inputs as commodities. The economics of a mistake in this space are unforgiving: a failed AAV lot delays patients and pushes filings; a missed fill–finish window leaves drug product waiting for a vial that is at someone else's line; an out of spec cell therapy batch forces expanded access shipments without revenue.

Figure 1. Modalities × "What's Clinical" heatmap. This heatmap compares four advanced therapy modalities (AAV in vivo; ex vivo lentiviral HSC; engineered immune cells; RNA therapeutics) across five clinical dimensions: Delivery, Analytics, Safety, Governance, and Capacity. Each cell shows an intensity score (0=None to 3=High) indicating how strongly that dimension drives development risk and operational planning for the modality. Darker cells mark primary drivers (e.g., AAV scores High for Delivery, Analytics, and Safety due to capsid selection, multi-attribute identity, and complement/TMA monitoring). Scores are qualitative syntheses of field practice (2020–2025); program-specific factors may shift intensities.

7) The money: where it came from, where it went, and what it priced

Cycles reveal preferences. In 2021, public windows were wide with roughly ~150 biopharma IPOs priced and large private rounds; by 2022, the window shrank to fewer than 50 IPOs and late stage valuations compressed, with flat and down rounds increasing as generalist capital retreated ^[56][57]. By 2023–2025, windows reopened selectively for companies that could move valuation with human data; private capital favored platform enablers and late clinical assets with line of sight to revenue.

IQVIA estimated cell and gene therapy spend at ~$5.9B in 2023 (+38% YoY) with 76 cumulative launches, numbers that support public equity patience ^[58]. Large capacity contracts (Samsung Biologics' $1.41B, 2025) showed that buyers pay premiums for validated end to end capability ^[53]. Private financing exemplars (Kriya's ~$900M) showed that enabling platforms that promise to reduce delivery/manufacturing risk can raise outsized rounds in risk off climates ^[59]. Strategic M&A told the same story from another angle: Pfizer–Seagen at $43B diversified post COVID revenue and bought control in a modality (ADCs) where manufacturing and late stage pipelines confer durable advantage ^[60].

Underneath, the financing mechanics depended on modality. AAV systemic programs required nine figure CMC and analytics budgets over the program life, plus debt like commitments for vector production and fill–finish. Ex vivo lentiviral HSC programs concentrated capex in GMP access and analytics and carried quasi fixed per patient costs (apheresis, conditioning, site readiness), with LTFU treated as a financed scientific asset rather than overhead. LNP mRNA programs used modular spend across sequences, leveraged platformable drug substance and shared drug product capacity, and moved gross margin and market access with lyophilization. Engineered cell programs combined plant/partner commitments with payer bridging cash for vein to vein cycles and outcomes based contracts that change recognition.

SPACs offered a cautionary coda. Enthusiasm in 2020–2021 gave way to redemptions and PIPE fatigue in 2022; only experienced sponsors with near term clinical value creation windows made the vehicle work ^[61][62]. The practical lesson is that companies with financing syndicates that can bridge to human data will survive; those that cannot will either reset or sell.

What did this cycle price? Certainty. Calendars that could be controlled (reserved slots, change control); products that were knowable (multi attribute identity); risks that were mechanistic (declared immunomonitoring and rescue); evidence that was longitudinal (registered LTFU); access that was designed (site readiness, coverage alignment). Discovery only stories without funded paths to delivery were discounted.

8) Looking forward: the questions that matter now

What does it mean to design for decades in a field that moves in months?

Perhaps the most honest underwriting question left is the simplest: does this team treat delivery, analytics, safety and governance as one story? If so, a breakthrough can become a business, a business can compound and value accrues to those who operate as if all five statements are true at once.

References