Manolis Kellis: Biology of Disease | Lex Fridman Podcast #133

The following is a conversation with Manolis Kellis, his third time on the podcast. He's a professor at MIT, and head of the MIT Computational Biology Group. This time, we went deep on the science, biology, and genetics. So this is a bit of an experiment. Manolis went back and forth between the basics of biology to the latest state-of-the-art in the research. He's a master at this. So I just sat back and enjoyed the ride. This conversation happened at 7:00 AM (laughs) , so it's yet another podcast episode after an all-nighter for me. And once again, since the universe has a sense of humor, this one was a tough one for my brain (laughs) to keep up, but I did my best, and I never shy away from a good challenge. Quick mention of each sponsor, followed by some thoughts related to the episode. First is SEMrush, the most advanced SEO optimization tool I've ever come across. I don't like looking at numbers, but someone probably should. It helps you make good decisions. Second is Pessimist Archive. They're back. One of my favorite history podcasts on why people resist new things, from recorded music to umbrellas, to cars, chess, coffee, and the elevator. Third is Eight Sleep, a mattress that cools itself, measures heart rate variability, has an app, and has given me yet another reason to look forward to sleep, including the all-important power nap. And finally, BetterHelp, online therapy when you want to face your demons with a licensed professional, not just by doing the, uh, David Goggins-like physical challenges like I seem to do on occasion. Please check out these sponsors in the description to get a discount and to support this podcast. As a side note, let me say that biology in the brain and in the various systems of the body fill me with awe. Every time I think about how such a chaotic mess coming from its humble origins in the ocean was able to achieve such incredibly complex and robust mechanisms of life that survived despite all the forces of nature that want to destroy it. It is so unlike the computing systems we humans have engineered that it makes me feel that in order to create artificial general intelligence and artificial consciousness, we may have to completely rethink how we engineer computational systems. If you enjoy this thing, subscribe on YouTube, review it with five stars on Apple Podcasts, follow on Spotify, support on Patreon, or connect with me on Twitter @lexfridman. And now, here's my conversation with Manolis Kellis. So your group at MIT is trying to understand the molecular basis of human disease. What are some of the biggest challenges in your view?

Don't get me started.

(laughs)

I mean-

Here we go again.

... understanding human disease is the most complex, uh, challenge in modern science. So because human disease is as complex as the human genome, it is as complex as the human brain, and it is in many ways even more complex, because the more we understand disease complexity, the more we start understanding genome complexity, and epigenome complexity, and brain circuitry complexity, and immune system complexity, and cancer complexity, and so on and so forth. So traditionally, human disease was following basic biology. You would basically understand basic biology in model organisms, like, you know, mouse and fly and yeast. You would understand sort of mammalian biology and animal biology and eukaryotic biology in sort of progressive layers of complexity, getting closer to human, phylogenetically. And you would do perturbation experiments in those species to see, "If I knock out a gene, what happens?" And based on the knocking out of these genes, you would basically then have a way to drive human biology, because you would, you would sort of understand the functions of these genes. And then if you find that a human gene locus, something that you've mapped from human genetics to that gene, is related to a particular human disease, you'd say, "Aha, now I know the function of the gene from the model organisms. I can now go and understand the function of that gene in human." But this is all changing. This is dramatically changed. So that, that was the old way of doing basic biology. You would start with the animal models, the eukaryotic models, the mammalian models, and then you would go to human. Human genetics has been so transformed in the last decade or two that human genetics is now actually driving the basic biology. There is more genetic mutation information in the human gene- genome than there will ever be in any other species.