iBiology Podcast

In their final talk, Walther and Farese explain how proteins are targeted specifically to the surface of lipid droplets.  This has functional consequences since proteins at the surface of lipid droplets govern lipid droplet growth and hydrolysis, and some of these proteins are associated with diseases. Farese and Walther end their talk by describing a number of diseases or physiological conditions that are now recognized as resulting from mutations in genes encoding proteins involved in lipid droplet formation. 

In Part 2, Walther and Farese explain in more depth how lipid droplets form in cells in an organized manner.  Triglycerides and other neutral lipids are made in the ER membrane.  They accumulate in localized regions of the membrane that grow towards the cytosol and eventually bud off into lipid droplets.  Farese and Walther describe experiments from their lab and others that have identified a protein complex in the ER membrane called LDAF1/Seipin that regulates where triglycerides localize and grow into mature lipid droplets. 

All life requires metabolic energy but energy supplies and demands change over time. For this reason, organisms have developed ways to store energy, predominantly as fat. Neutral lipids are packaged into lipid droplets, small organelles found in most eukaryotic cells and in some prokaryotes. Lipid droplets play a critical role in an organism’s physiology; too many lipid droplets can result in obesity and too few in metabolic disease.  In their first video, Drs. Farese and Walther introduce us to lipid droplets and explain their importance in cellular biology.

DNA synthesis that occurs during repair is much less accurate than normal DNA replication. Using the yeast mating type switching system, Haber’s lab identified base pair substitutions, frame shifts and other mutations that occur when the newly synthesized strand dissociates from the template strand during homologous recombination.  Interestingly, Haber found that sometimes the newly synthesized strand will “jump” to a related but divergent template, even on another chromosome, and then jump back to complete the repair. Further experiments showed that this happens because the repair polymerase falls off the template with a very high frequency. Understanding why this occurs may help us to decipher the complex chromosomal rearrangements associated with certain human diseases.

Esvelt’s second talk focuses on strategies to allow for the safe implementation of localized gene drive technologies that do not spread indefinitely. Daisy drive systems are made up of multiple elements connected like a daisy chain such that each causes the next to be preferentially inherited. They are designed to be self-exhausting by losing elements with each generation, thereby limiting spread. This technique has multiple applications such as removing an invasive species from one area without impacting the same species in its native habitat. Esvelt explains that daisy-drive stability might be tested in a species such as C. elegans where hundreds of generations can be grown in a short period of time. His lab is also developing technologies to reverse any unwanted genetic changes that might be introduced via gene drive. Once again, Esvelt emphasizes the importance of community input into any gene alteration projects. Although it does not currently involve gene drive, he uses the “Mice Against Ticks” project that seeks to prevent tick-borne diseases on the islands of Nantucket and Martha’s Vineyard as an example.

Evolution has selected wild organisms to be extremely well adapted to their environment. Because most genetic changes introduced by humans divert the resources of the organism to benefit humans, such mutations are typically eliminated by natural selection in the ancestral habitat. In his first talk, Dr. Kevin Esvelt explains how self-propagating CRISPR-based gene drives can be used to spread genetic alterations through wild populations, potentially impacting all organisms of the target species. Gene drives could be used to benefit public health, the environment, agriculture, and animal well-being. However, real-world use may incur ecological risks, and even research involving self-propagating gene drive systems may risk public trust in science and governance given the possibility of accidental spread. Esvelt explains how to minimize risk and discusses the importance of engaging communities in planning any projects which may affect them.

When an infectious disease outbreak happens, medical workers and public health officials mobilize, but there are also teams of researchers that snap into action. Dr. Tracey Goldstein and Dr. Koen Van Rompay are both actively involved in different initiatives to find answers surrounding the COVID-19 epidemic. They talk about the process of studying coronaviruses and other infectious diseases, the steps taken once an outbreak hits, and the ways in which this process could change for the better. The changing world we live in makes predicting outbreaks a challenge, but each one teaches us something new about how to understand and to respond to the next.

In his third talk, Clevers describes how organoids can guide our understanding of disease progression in cancer. In addition, using Cystic Fibrosis and cancer as examples, Clevers shows how organoids can be used to predict therapeutic outcome in patients.

In his second talk, Clevers shows how one can apply what we have learned from developing gut organoids to generate mini-organs for other epithelial tissues, like liver and lung. Clevers shows that these organoids have a similar expression profile as well as structural characteristics to those observed in real tissue. In addition, he shows how this technique can be used to generate non-mammalian organoids, like the development of venom gland organoids from snake venom gland tissue. As Clevers explains, such organoids can be used to discover possible novel therapeutics, including new anti-venom serum.

In his first talk, Dr. Hans Clevers provides a historical perspective on the discovery of adult stem cells in the gut. They identified a Wnt-dependent, rapid proliferating population of cells at the bottom of the crypt which seemed to be important for generating all epithelial cells in crypts and villi, and they hypothesized that these were gut stem cells. By using the Lgr5 gene as a marker, the Clevers’ lab confirmed that these long-lived cells were indeed the gut stem cells by showing that they were able to generate all of the cell types of the gut epithelium throughout life. Clevers characterizes the gut stem cells and its progenitors, and explains how his lab developed a technique to grow from a single stem cell an organoid or mini-organ, a structure that recapitulates the normal structure of the gut.