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

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00:00:00 - 01:00:00

Manolis Kellis is a biologist who studies disease. He discusses the role of genetics in disease, and how human genetics has helped to identify which genomic regions are associated with Alzheimer's disease. He also discusses the different levels of epigenetics, including DNA, gene expression, and cellular activity.

00:00:00 Manolis Kellis is a professor at MIT and head of the Mit computational biology group. In this conversation, he goes over the challenges of understanding human disease at the molecular level, from perturbation experiments in model organisms to human genetics. The rapid advances in human genetics have revolutionized our understanding of human disease, and suggests that basic biology may now be driven more by genetic mutation than by traditional animal models.
00:05:00 Manolis Kellis discusses how mutations allow scientists to understand disease mechanisms. He describes how genetic epidemiology is used to study the connection between changes in the genome and phenotypic differences in humans. He also describes how animal models can be used to simplify the puzzle of understanding how small perturbations can lead to disease in a stable way.
00:10:00 Manolis Kellis discusses the importance of power analysis in the field of genetics, and how it can help researchers determine which parts of the genome have a strong effect on disease. He also mentions the use of large, well-phenotyped cohorts in this process.
00:15:00 Manolis Kellis is a biologist who specializes in the study of disease. He discusses the role of genetics in disease, and how human genetics has helped to identify which genomic regions are associated with Alzheimer's disease.
00:20:00 Manolis Kellis discusses the different levels of epigenetics, including DNA, gene expression, and cellular activity. He explains that the earlier in the epigenetic pathway that alterations are detected, the better chance there is of successful treatment.
00:25:00 Manolis Kellis discusses the importance of understanding the genetic origins of diseases, which can affect both the quality of life and the sheer number of deaths they cause. He discusses the top three killers in the US, as well as other important diseases.
00:30:00 Manolis Kellis discusses the importance of understanding the biological mechanisms leading to disease in order to intervene. He argues that understanding the genetic component can have a huge impact even on the environmental component.
00:35:00 Manolis Kellis discusses the role of genetic variation in disease. He says that different genes have different levels of impact on disease, and that those with no variation are the most important. He goes on to say that failure fast, or the ability to fail quickly and move on, is an evolutionary principle that has been successful for mammals. Finally, he talks about how genetic variation can be used to target treatments to specific individuals.
00:40:00 Manolis Kellis discusses how genetics affects disease, discussing how some genetic variants have a strong effect on the disease, while others have a weaker effect. He also discusses the concept of genetic exceptionalism, which is the belief that genetics is different from everything else and is a determinism. He touches on the topic of age-related macular degeneration (AMD) and how genetics has helped to understand the cause and progression of the disease. Finally, he talks about how complement and schizophrenia are two recent examples of how genetics has impacted disease.
00:45:00 Manolis Kellis discusses how the immune system has been co-opted to play many different roles across the body, including the role in synaptic pruning. This research led to the development of the epigenomics roadmap, which showed which genetic variants are associated with diseases in different tissues.
00:50:00 Manolis Kellis discusses how his research has uncovered a connection between tissues and diseases, showing that understanding the tissues involved can lead to the development of better treatments.
00:55:00 Manolis Kellis discusses the current state of genetics and the ways in which it is revealing unexpected connections between different diseases. He notes that, as genetics advances, specialists in different diseases will need to be versed in it in order to solve the underlying circuitry. This is an inevitable trend, and one that will require a unified approach from all disciplines working on disease.

01:00:00 - 02:00:00

Manolis Kellis discusses the biology of disease, specifically how different genetic variants can be associated with diseases such as Huntington's, Alzheimer's, and other psychiatric disorders. He explains that convergence, or the tendency for multiple genetic variants to impact a single biological process in the same way, is a saving grace for the field of genetics. He also discusses how Crispr technology can be used to manipulate genes and how mass-producible technologies can be used to generate thousands of hypotheses about disease.

01:00:00 Manolis Kellis discusses the biology of disease, focusing on Huntington's disease, Alzheimer's, and other psychiatric disorders. He discusses the role of genetics and epigenetics in disease, and how his group has developed a deep understanding of how individual cells and tissues interact to create systemic disease. He describes the path to developing cures for these disorders, emphasizing the need for cross-cutting expertise across many genes.
01:05:00 Manolis Kellis explains that genes don't always cause diseases, and that most variants that are associated with diseases don't actually impact the protein they're supposed to. He goes on to say that this is difficult to do, and that scientists still don't have a good understanding of disease. He finishes by suggesting that scientists continue to embrace the wholeness of the genetic circuitry, and that scientists start by understanding the tissue and the individual.
01:10:00 The video discusses the concept of convergence, which refers to the tendency for multiple genetic variants to impact a single biological process in the same way. Manolis Kellis discusses how this happens in the context of diseases such as schizophrenia and Alzheimer's, and how the convergence of multiple genetic variants is a saving grace for the field of genetics.
01:15:00 The video discusses the biology of disease, specifically how different genetic variants can be associated with obesity. Mesenchymal stem cells are highlighted as a key player in this process, as they are responsible for the generation of brown and white fat cells. These cells also play a role in the regulation of energy intake and expenditure.
01:20:00 Manolis Kellis discusses the steps of identifying a genetic variant as the cause of a disease, determining the relevant tissue based on global enrichment, and tracing the variant to the genes that mediate its biological process. He goes on to discuss the use of pharmaceutical therapeutics against the variant or the expression of the target genes.
01:25:00 Manolis Kellis discusses the three links between genetics and disease- the physical, the genetic, and the activity. He explains how Crispr technology can be used to explore these links in more detail.
01:30:00 The genome editing tool Crispr has revolutionized biology by allowing scientists to cut and repair DNA more easily. The downside is that it is a difficult process to design the right set of proteins to do this.
01:35:00 Manolis Kellis discusses the biology of disease and how Crispr technology can be used to manipulate genes. He points out that Crispr technology is easier to use than old school methods of gene engineering, and that by linking a locus to a target gene, researchers can begin to understand the function of those genes. Steps five and six of the Crispr process involve finding the target gene and understanding what it does, which can then be used to manipulate it for desired effects.
01:40:00 This video introduces the concept of the nucleus, prokaryotes, and eukaryotes, and describes the differences between these three groups of organisms. It explains that eukaryotes have a nucleus and compartmentalization, and that they also have organelles, such as chloroplasts. It discusses the endosymbiotic event that led to the development of mitochondria, and the role that these organelles play in the body. The video also discusses the process of thermogenesis, and how people who are unable to thermogenize may still be able to consume food and burn calories.
01:45:00 Manolis Kellis discusses how obesity is caused by a combination of genetics and environmental factors. He describes how recent advances in technology have made it possible to identify and target the genetic factors that contribute to obesity. The author is excited about the future of obesity research, which will involve systematic studies of thousands of loci.
01:50:00 Manolis Kellis, a biologist at the University of Exeter, discusses how his team has developed technologies for testing millions of genetic variants at a time. One of these technologies is massively parallel reporter assays, or mpra. This allows for the testing of tens of thousands of variants at a time on a single plate using a microarray. The advantages of using mpra over traditional methods include automation and the ability to test variants in parallel.
01:55:00 Manolis Kellis discusses the biology of disease, explaining that scientists can use mass-producible technologies to generate thousands of hypotheses about disease, and then test them all. Next, he discusses single-cell RNA sequencing, which is a more recent technology that allows scientists to look at a single cell's RNA expression levels.

02:00:00 - 02:30:00

In this video, Manolis Kellis discusses the biology of disease and how new technologies can be used to study and treat diseases. He talks about the role of DNA and epigenetics in disease, and how computational biology can be used to design experiments that are less reliant on traditional biology. He also discusses the potential for artificial intelligence to help with drug design and personalized medicine.

02:00:00 The three main technologies used for single cell RNA sequencing are parallel reactions, lipid droplets, and barcodes. The first two technologies allow for the amplification of RNA, while the third technology allows for the sequencing of single cells and the identification of transcriptional variation across different brain cell types.
02:05:00 Manolis Kellis, a biologist at the University of Utah, discusses how his team is using DNA and epigenetics to study disease. They use DNA profiling and epigenetics to look for enhancers that are associated with different genes and figure out how these enhancers are related to each other. They are also working to design experiments that are less reliant on traditional biology and more reliant on computing.
02:10:00 Manolis Kellis discusses how computational biology groups are focused on the biology of disease, and how the field is moving closer to curing some of the diseases humanity has faced for centuries.
02:15:00 This video discusses the potential of new technologies to manipulate cells and diseases. These technologies include genomics, cell type identification, and synthetic biology. These technologies are being used to study schizophrenia and Alzheimer's, two diseases with complex cell signaling.
02:20:00 This video discusses how different genetic variants, common and rare, play a role in Alzheimer's disease, and how single-cell RNA sequencing can be used to identify these variants. By understanding the role these variants play in disease, researchers may be able to develop better treatments for Alzheimer's.
02:25:00 Manolis Kellis discusses the biology of disease, explaining that humans are different from other species in many ways, including having more cells, a more efficient brain, and a longer lifespan. He goes on to discuss how these differences can lead to problems, such as Alzheimer's disease, cancer, and other brain-related disorders. He also talks about the potential for artificial intelligence (AI) to help with drug design and personalized medicine.
02:30:00 In this conversation, Manolis Kellis discusses the role of molecular biology in disease management and the importance of understanding the complex wiring of genes to phenotypes. He also discusses the concept of on-target side effects and off-target side effects, and how intervention at the networks level could be more effective than targeting single genes. Haruki Murakami's quote about human beings being nothing but carriers for genes is poignant and relevant.