Reflection of the last weeks

• Never had a pipette in hand before this - got feeling for how archaic following wetlab protocols per hand is

  • Realized that robotic wetlab infrastructure is needed for high throughput research

• Realized limitations of brain organoids

  • Vascularization
  • Maturation
  • Blood brain barrier modeling
  • Modeling of the lymbic system/stem brain - currently focused on prefrontal regions

• Coming weeks:

  • Researching differences between mouse/human brain
  • Researching continuous hormone measurement systems
  • In silico modeling of nootropic compounds

The bigger picture:

• 7 billion people drink caffeine
• 2 billion knowledge workers globally depend on cognitive enhancement
• Knowledge work hubs like the Bay Area, Boston/NYC & London are known for psychoactive drug usage
• Neurodiversity leads to creativity:
  • Paul Erdős: Mathematical genius who relied on amphetamines for decades
  • Francis Crick: Co-discoverer of DNA structure, reportedly used LSD
  • Kary Mullis: Nobel Prize winner for PCR, advocated for LSD's cognitive benefits
  • First banking houses being created around coffee houses in London (Lloyd's of London)
• ~700 substances show potential for brain health & cognitive enhancement
• Market opportunity: Knowledge workers represent the highest-value demographic globally

The problem: Feedback loops - current nootropic/supplement space is not personalized or data-driven

Current Issues:

• No personalized optimization: One-size-fits-all approach ignores genetic polymorphisms
  • COMT gene variants affect dopamine metabolism (fast vs slow metabolizers)
  • 5-HTTLPR serotonin transporter gene variations
  • BDNF gene polymorphisms impact neuroplasticity
• Lack of real-time feedback: Users have no objective measures of cognitive improvement
• Poor dose optimization: No data on individual metabolic rates or receptor sensitivity
• Tolerance and adaptation: Brain's homeostatic mechanisms reduce effectiveness over time
• Questionable compound quality: Unregulated supplement industry with inconsistent purity

Markers we need to track:

• Neurotransmitter levels: Dopamine, serotonin, norepinephrine, acetylcholine
• Functional markers: Cerebral blood flow, glucose metabolism, neural oscillations
• Inflammatory markers: CRP, IL-6, TNF-α
• Neurotrophic factors: BDNF, NGF, GDNF
• Cognitive performance: Working memory, processing speed, attention span
• Metabolic markers: Blood glucose, lipid profiles, oxidative stress indicators

Using brain organoids to measure the effects of nootropic compounds

Methodology:

• iPSC-derived brain organoids: 4-month cultivation period reaching ~200,000 neurons
• Multi-electrode arrays (MEAs): Real-time electrical activity monitoring
• Compound injection protocols: Precise dosing using filtration systems
• High-throughput screening: Test 100+ compounds simultaneously
• Assembloids: Connected organoids modeling different brain regions
• Vascularized organoids: 3D-bioprinted blood vessels for improved nutrition

What we measure:

• Electrical activity: Action potential frequency, network synchronization
• Metabolic changes: Glucose consumption, oxygen utilization
• Neurotransmitter release: Real-time monitoring via biosensors
• Morphological changes: Dendritic growth, synaptic density
• Gene expression: RNA sequencing for pathway activation

Current challenges with brain organoids

Fundamental limitations (4-month organoids vs 21-year-old brain):

• Size: 2-4mm diameter vs 1,400g human brain
• Neuron count: 50K-200K vs 86 billion neurons
• Development stage: Equivalent to 14-24 week fetal brain
• No sleep / wake cycle: Substantial for learning / neuroplasticity in humans
• Missing cell types: Especially limited microglia
• No myelination: <1% vs >50% myelinated axons in adult brain
• Simplified neurotransmitter systems: Only 20-30% of adult complexity
• No blood-brain barrier: Overestimates drug penetration
• Missing brain regions: No hippocampus, basal ganglia, cerebellum

Specific nootropic screening limitations:

• Stimulants (Modafinil, Adderall): Require intact dopaminergic pathways
• Cholinesterase inhibitors: Limited without mature cholinergic innervation
• AMPA modulators: Reduced efficacy without complex dendritic processing
• Noradrenergic modulators: Virtually no target structures present

Algernon's Law

Should we interfere with evolutionary processes?

• Yes - provide energy and let systems overdrive: Use additional energy resources
• Evolutionary mismatch theory: Modern abundance vs ancient scarcity-adapted brains
• Precedent exists: Caffeine consumption shows 7 billion people already enhance cognition
• Optimization vs overclocking: Work within biological constraints, not against them
• Energy availability: Modern nutrition provides unprecedented metabolic resources

Evidence for enhancement potential:

• Genetic diversity: Natural cognitive variation shows improvement possibility
• Training effects: Brain plasticity demonstrates enhancement capacity
• Pharmacological precedent: Existing nootropics prove modifiability
• Nutritional optimization: Proper micronutrients already enhance performance

Neurotypes

Genetic-based personalization:

• COMT gene variants:
  • Val/Val (fast metabolizers): Need higher dopamine doses
  • Met/Met (slow metabolizers): Sensitive to overstimulation
• 5-HTTLPR polymorphism:
  • Short allele: Higher anxiety, benefits from serotonergic support
  • Long allele: Lower baseline anxiety, different optimization needs
• BDNF polymorphisms:
  • Met carriers: Reduced neuroplasticity, need enhancement support
  • Val/Val: Normal plasticity, standard protocols effective

Functional neurotypes:

• High stimulation seekers: Dopaminergic system optimization
• Anxiety-prone individuals: GABAergic and serotonergic support
• Creative types: Default mode network modulation
• Analytical thinkers: Frontal lobe optimization
• Memory-focused: Cholinergic system enhancement

Compounds case studies

• Lions Mane: Neurogenesis and dendritic growth - Mechanism: Nerve Growth Factor (NGF) and BDNF stimulation
• Alpha-GPC: Cholinergic precursor, 40% choline by weight
• Bacopa Monnieri: Memory enhancement, stress reduction
• Rhodiola Rosea: Adaptogen, fatigue reduction

Other related problems I am exploring:

• Effectiveness / difference in usage of microneedles for compounds delivery vs traditional pills, which go through digestive tracks.
• Genetic neurotypes
• Non-invasive ways to measure neurotransmitter levels in humans.
• Modalities to measure neurotransmitter levels in-vivo in mice and monkeys.
• Exploration of monkey brain tissue and keeping it alive for longer than 4 hours (current state of the art in research) - requires "brain in the jar technology" - think the CL1 from Cortical Labs but with vascularization.