Manolis Kellis — Professor at MIT and head of the MIT Computational Biology Group. He studies the molecular basis of human disease by mapping the genome, epigenome, and gene-regulatory circuitry at single-cell resolution.
The gist
Manolis Kellis walks Lex Fridman through how human genetics, rather than animal models, now drives the basic biology of disease. He explains that 93% of disease-associated variants fall outside genes, so understanding disease requires decoding the genome's long-range regulatory circuitry across tissues and cell types. Using his lab's six-step pipeline, he details how the strongest obesity locus (FTO) actually controls distant genes (IRX3/IRX5) governing fat-burning thermogenesis. He describes massively parallel technologies (MPRA, CRISPR perturbation, single-cell RNA/epigenome sequencing) that let researchers test thousands of hypotheses at once, and argues we are entering an era of systems medicine that will fundamentally alleviate disease.
Big reveals
- Alzheimer's is roughly 79% heritable, meaning genetics alone explains most of its incidence.
- His team found ZERO enrichment for Alzheimer's variants in brain neurons, astrocytes, or oligodendrocytes, pointing instead to immune microglia.
- The strongest obesity locus, FTO, does not implicate the FTO gene at all but controls IRX3 and IRX5 over a million nucleotides away.
- Kellis is a homozygous carrier of the rs1421085 risk allele, so he cannot turn on thermogenesis and is genetically predisposed to obesity.
- Editing one nucleotide out of 3.2 billion with CRISPR flipped cells between an obese and a lean phenotype like a switch.
- An immune complement pathway unexpectedly underlies both age-related macular degeneration and schizophrenia via synaptic pruning.
- Kellis predicts the next few years will bring the most dramatic manipulation of human biology in the history of humanity.
Things worth remembering
- Every human carries about six million genetic variants, each a tiny natural perturbation experiment.
- Only 1.5% of the human genome codes for proteins; the other 98.5% does not.
- The number one killer is heart disease (650,000 Americans/year), then cancer (600,000), with accidents far behind.
- CRISPR originated as a bacterial immune system and was first studied by the yogurt industry to make cultures more virus-resistant.
- Mitochondria arose from an ancient engulfed organism via endosymbiosis and retain only 13 genes.
- About 42% of European chromosomes carry a fat-storage predisposition likely selected during ice-age food scarcity.
- Kellis's team generated 10 million brain cells in one year across a dozen disorders to map regulatory circuitry.
- In the famous human-versus-horse endurance race, the human outlasts the horse, showing our unique metabolic adaptation.