Jul 31, 2020, 9:28 AM ETInterview

Manolis Kellis: Human Genome and Evolutionary Dynamics | Lex Fridman Podcast #113

Life as a Digital Computer: Manolis Kellis characterizes life as the "first digital computer," where information is stored discretely (unlike analog concentrations) to prevent information loss over generations, a mechanism discovered by Mendel.
Discrete vs. Continuous Traits: While Mendelian inheritance is discrete, continuous traits (e.g., height) arise from the additive effect of thousands of genes, each contributing a minute variation, a concept clarified by Ronald Fisher.
99.9% Genetic Similarity: Any two humans are 99.9% identical, a fact Kellis argues should reduce conflict and war, despite siblings differing by millions of genetic locations.
Vertical vs. Horizontal Inheritance: Humans possess unique "horizontal inheritance" (culture, ideas, education) transmitted laterally, whereas other species rely primarily on "vertical inheritance" (genetic instincts); this is enabled by neoteny, the delayed maturation of the human brain allowing for prolonged learning.
Democratization of Knowledge: The internet facilitates the rapid, global spread of information (e.g., the SARS-CoV-2 genome was sequenced and shared within weeks of the first sample), though this brings the risk of abolishing respect for expertise.
Epistemology in Education: Kellis advocates that education must prioritize epistemology (the methodology of acquiring knowledge and verifying sources) alongside rote knowledge to navigate the "democratization of information."

Novel Gene Discovery: Kellis's group used evolutionary signatures to identify ORF10 as a non-coding RNA structure rather than a protein-coding gene and discovered a previously unknown gene nested within ORF3A.
Evolutionary Rates: The S1 spike protein (responsible for host attachment) evolves rapidly ("gas pedal"), whereas the polymerase and nucleocapsid proteins evolve slowly ("brake pedal") due to internal functional constraints.
D614G Mutation: The D614G mutation in the S protein represents a significant adaptation for human-to-human transmission, shifting from near 1% to 90% frequency in outbreaks, as it was never observed in the bat reservoir.
Virus "Intelligence": Kellis rejects the notion of virus intelligence, attributing their success to "stupid mutation" and "ruthless selection" acting as a brute-force search engine across billions of parallel infections.
Virus and Host Co-evolution: Viruses have historically contributed to mammalian evolution by inserting binding sites into host genomes, co-opting viral sequences for regulatory functions; he asserts the virus is not trying to kill its host, as killing the host prevents further spread.
Natural vs. Engineered Origin: Kellis states the evidence strongly supports a natural origin, citing that the S1 protein's recombination patterns are typical of natural coronavirus evolution and that the source genome was a variant never previously seen in humans, making laboratory engineering unlikely.

Content-Based Indexing: Unlike computers that use "goto" instructions (memory addresses), the genome uses "content-based indexing" where regulatory motifs act as tags to recruit machinery, allowing for robust, fault-tolerant systems.
Robustness Over Perfection: Biological systems prioritize robustness and resilience (tolerating 20% mutation with no effect) rather than perfection; engineering should emulate this by embracing messiness and breaking local optima to reach new evolutionary peaks.
Whole Genome Duplication: Kellis explains that whole genome duplication is a "messy" evolutionary event that initially creates redundancy; over time, ~90% of duplicated genes are lost, while the remaining 10% specialize for environmental adaptation and complexity.
The Role of Misinterpretation: Ambiguity in language and biology is a feature, not a bug; just as misinterpretations in conversation fuel creativity, noise in neural signaling allows biological systems to escape local maxima and innovate.
Brain-Computer Interfaces (BCI): Kellis predicts BCIs will succeed via training the human (output side) to match machine input rather than decoding complex thoughts (input side); humans will learn to "speak" machine language through neural plasticity, similar to learning to control artificial limbs.

The "Meaning of Life" Symposium: Kellis organized an event with 42 colleagues where each gave a different answer, culminating in a linguistics professor's Pythian response: "Become one" (interpreted as becoming one with the world as a child, becoming one with perfection in tasks, and becoming one with others).
The Quest as Meaning: Kellis posits that the "quest for meaning" itself, the constant pursuit of the sublime and human connection, is the fundamental purpose of life.
Utility and Gratitude: He derives profound pleasure from feeling useful and exhausted by intellectual work, viewing this utility as a core component of a meaningful existence.
Parenting as Completion: Kellis describes raising children as the ultimate act of "creating human life," a decades-long process of compassion and vulnerability that completes the parent's own biological and emotional hardware.
Future Sensory Capabilities: He speculates that humans may soon develop new "senses" via technology to perceive currently invisible physical phenomena (e.g., gravitational waves, axions), similar to the historical evolution of photoreception.
Free Will and Determinism: Kellis views free will as a complex interplay of chemical reactions and environmental constraints, suggesting that while the system may be deterministic, the sheer number of variables makes long-term prediction impossible (chaos theory).