VI. Biological Strategies to Expand Human Intelligence: Neurotrophins

Mitigating the Existential Risk of AI: Enhancing Human Intelligence beyond its Native Biological Potential

Table of Contents:

I. Overview and Introduction | II. The Inevitability and Existential Risk of Artificial General Intelligence | III. Understanding Human Intelligence | IV. Reaching vs. Expanding Biological Potential | V. Biological Strategies to Expand Human Intelligence: Neurotransmitter Modulation | VI. Biological Strategies to Expand Human Intelligence: Neurotrophins | VII. From Neurons to AI: The Surprising Symmetry of Emergence | VIII. Biological Strategies to expand Human Intelligence: Neurogenesis

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AI’s depiction of a neuron in the brain. Midjourney.

RECAP

This series of posts has discussed the need to improve human intelligence to mitigate the existential risk posed by artificial general intelligence (AGI). In the previous post, we discussed how neurons (the functional component of the brain) use neurotransmitters for communication and how their modulation offers one potential pathway for improving cognitive function. In this post, we delve into neurotrophins, their function in the brain, their impacts on intelligence, risks, current research, and future opportunities.

NEUROTROPHIN INTRODUCTION AND OVERVIEW

The brain is composed of billions of neurons and trillions of synapses (connections between neurons). These neurons require specific signals to mature, grow, produce new synapses, etc. In the body, these types of signals are typically sent by soluble proteins that bind to a cell receptor and initiate an associated signaling cascade to perform a function. Neurotrophins are a family of regulatory proteins that support nearly every key process including development, growth, connectivity, and adaptability of neurons (Lu, 2014). They do this by binding to receptors on neural cell surfaces. Some of these neurotrophic signaling proteins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). If the brain is compared to a garden, the neurotrophins would be an essential part of the fertilizer.

Table 1. Neurotrophins and small molecule agonists.

MECHANISMS

Neurotrophins exert their effects by binding to specific receptors on neural cell surfaces. The main neurotrophin receptors are the tropomyosin receptor kinases (Trk) and the p75 neurotrophin receptor (p75NTR) (Casaccia-Bonnefil, 1998). Each neurotrophin binds preferentially to certain Trk receptors. For example, BDNF specifically binds to and activates TrkB receptors. Upon binding, the neurotrophins trigger intracellular signaling cascades that support neuronal survival, growth, differentiation, and synaptic plasticity.

BDNF binding to TrkB is particularly important for long-term potentiation, the strengthening of synaptic connections between neurons that is vital for learning and memory formation. The binding initiates the activation of proteins that remodel the structure and function of synapses, enhancing their signaling capacity. In this way, BDNF facilitates the neural circuit changes needed for memory encoding.

By tuning the activity of neurotrophin signaling pathways, we may be able to promote optimal neural health, connectivity, and adaptability. However, more research is needed to fully elucidate the complex intracellular mechanisms involved.

IMPACTS ON INTELLIGENCE

Given the roles of neurotrophins in neuronal growth, connectivity, and synaptic plasticity, modulating their activity could potentially enhance cognitive abilities. However, the effects on healthy humans are still speculative based on limited research.

Animal studies suggest increasing BDNF levels may improve learning and memory capacity. This was demonstrated several key studies showing BDNF signaling is critical for spatial memory formation and recall (Mizuno, 2000) and general learning (Yamada, 2002). However, this has not been conclusively demonstrated in humans. Observational studies show correlations between higher naturally occurring BDNF levels and better performance on cognitive tests, but causation cannot be inferred (Dincheva, 2016).

Initial clinical trials of small-molecule BDNF mimetics like 7,8-DHF in humans have yielded mixed results. Some studies reported minor cognitive improvements, while others found no differences compared to placebo. Much larger rigorously controlled trials are needed to truly determine efficacy.

If neurotrophin signaling could be finely tuned within safe parameters, it is hypothetically possible synaptic plasticity and neurogenesis could be optimized. This could strengthen the encoding of memories, increase cognitive flexibility, improve learning ability, and even enhance fluid intelligence. However, we are far from understanding the risks and optimal dosing required.

RISKS AND CHALLENGES

While neurotrophin modulation is promising, there are substantial challenges that must be addressed before it can be applied safely. Delivering neurotrophins to the brain is difficult because they cannot readily cross the blood-brain barrier using standard methods. Developing novel delivery mechanisms to enable sufficient concentrations to reach neural tissues, without adverse effects elsewhere in the body, will be critical. Additionally, each neurotrophin has multiple receptor targets that trigger complex signaling cascades we do not yet fully understand. More research is needed to determine how to activate select pathways to achieve targeted effects. Excessive or uncontrolled neurotrophin signaling could potentially promote synapse formation in detrimental ways or broadly alter neural network function. Dosing and activity would need to be tightly regulated. There is also likely individual variation in optimal dosing and sensitivity arising from genetic and environmental factors. Personalized approaches attuned to a person’s neurotrophin levels, receptor profiles and sensitivities would be essential. Finally, the ethical dimensions require analysis regarding the risks of coercive or mandatory use, equitable access, and unintended societal consequences. Enhancing cognition safely amidst the complexity of the human brain will require overcoming numerous hurdles through step-wise scientific inquiry into both the benefits and risks.

CURRENT RESEARCH

While neurotrophins themselves are well studied, research on leveraging them to enhance cognition is quite nascent. Most human studies have been small pilot trials of compounds like 7,8-DHF in patients with neurological disorders, showing minimal cognitive effects. Rigorous placebo-controlled trials in healthy adults are lacking. Beyond TrkB agonists, other approaches being explored include viral vector delivery of neurotrophin genes, and compounds that inhibit neurotrophin breakdown or increase their endogenous production. But most modalities are still preclinical. Challenges around delivery, dosing, and monitoring effects in the human brain remain. Advances in neuroimaging, nanotechnology, and machine learning algorithms to design molecules may accelerate progress. However, substantive validation of safety and efficacy likely remains years to decades away. We have made promising starts, but modulating neurotrophins to enhance cognition safely remains an immense challenge requiring extensive further research across multiple disciplines.

OPPORTUNITIES

Improved Delivery Mechanisms: Neurotrophins cannot cross the blood-brain barrier through traditional delivery routes. Promising solutions like nanoparticles coated with transferrin or rabies virus glycoproteins are being tested. Lipid-based carriers, peptide vectors, and focused ultrasound techniques also aim to temporarily open the barrier for delivery. Refining such platforms could enable targeted neurotrophin delivery for research and therapeutics.

Small Molecule Analogs: Because of their small size, mimetic compounds can readily cross the blood-brain barrier, unlike large neurotrophin proteins. By designing small molecules that bind to neurotrophin receptors, we can potentially activate the same signaling pathways to elicit similar neuronal effects. However, initial attempts like 7,8-DHF exhibit poor receptor specificity and drug-like properties. Optimizing such mimics to more selectively target specific Trk receptors could yield better drug candidates. Medicinal chemistry insights into structure-activity relationships and comparisons to natural neurotrophins can inform efforts to design improved mimetics with higher receptor potency and blood-brain barrier permeability.

AI for Drug Discovery: The process of identifying and optimizing new drug compounds is incredibly challenging due to the vast chemical search space. There are an estimated 10^60 potential small molecule structures, making comprehensive experimental screening infeasible (Bohacek, 1996). Furthermore, identifying small molecule candidates that function in place of traditional neurotrophin proteins has not been successful, even after screening 40,000 compounds (Boltaev, 2017). However, AI tools like generative deep learning models and molecular dynamics simulations, such as AlphaFold2, can rapidly predict promising new molecular structures and protein-binding affinities in silico (Jumper, 2021). This allows researchers to focus experimental testing on the most viable small-molecule candidates from AI-generated compound libraries. Overall, combining computational predictions with lab validation could fast-track the development of improved neurotrophin analogs.

Tool Building for Neurotrophin Assessment: Validating neurotrophin enhancement requires specialized tools. Advanced neuroimaging could visualize neurotrophin receptor expression patterns and signaling dynamics in response to mimetics. Sensitive behavioral tests for synaptic plasticity and hippocampal-dependent learning could confirm pro-cognitive effects. Blood biomarker assays could help monitor treatment response. Computational models of neurotrophin signaling pathways and neuronal growth could predict therapeutic windows and side effects. Developing novel techniques tailored to neurotrophins will be essential to guide modulation therapies and determine their efficacy.

Figure 1. Potential pipeline for neurotrophin development. This pipeline would begin with the identification of neurotrophin and target receptor amino acid sequence. This would be fed into a machine learning algorithm (e.g., AlphaFold2) to determine candidate molecules for activating the receptor. High throughput screening would then be utilized for initial assessment of if small-molecule binding to target receptor. Small molecules with hits would move onto functional assessment in vitro for improving specified features on the neuron. Finally, top candidates would move onto animal screening with behavioral tests utilized to determine cognitive improvements.

CONCLUSIONS

Neurotrophin therapies offer theoretical promise for enhancing cognition but face substantial hurdles requiring careful science to address. While small molecule mimetics and emerging technologies could accelerate progress, rigorous research across disciplines is essential to validate any safe and effective application. As we continue exploring avenues to nourish neuronal growth, our next chapter will delve into the potential of modulating neurogenesis. Though neurotrophins support the vitality of existing neurons, generating new neurons could also expand cognitive capacity. However, like neurotrophin modulation, realizing any such benefits demands patience, prudence, and verification through incremental scientific inquiry. The fruits of our labor await uncovering, not speculation.

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