iBiology Podcast

Littman explains that different commensal microbes in our gut elicit different T cell responses - either pathogenic or non-pathogenic. His lab is beginning to identify the pathogens and decipher the pathways that determines the host T cell response. This research has important clinical relevance since a cancer patient’s microbiota may help determine their response to chemotherapy and immunotherapy. Microbiota that induce non-pathogenic Th17 cells and regulatory T cells are protective against autoimmunity but may decrease anti-tumor immunity, while microbiota that contribute to autoimmunity may enhance anti-tumor T cell responses.

In mammals, sex is determined by a pair of unequal sex chromosomes. Genetically male mammals have an X and a Y chromosome while genetically female mammals have two X chromosomes. The X chromosome is many times larger than the Y chromosome. To compensate for this genetic inequality, female mammals undergo X chromosome inactivation in which one of the X chromosomes is randomly chosen to be silenced. X chromosome inactivation has been studied for over 50 years both because it is a physiologically important event and because it is an excellent model for studying epigenetic silencing of genes by long non-coding RNAs. In her first talk, Dr. Jeannie Lee gives an overview of the steps a cell must go through during X inactivation. These include “counting” the X chromosomes, deciding which X chromosome to inactivate, initiating the inactivation and spreading it across the chromosome, and finally maintaining inactivation of the same X chromosome for the rest of the life of the organism.

Lee elaborates on the early steps of X inactivation. Very early in development, cells “count” the number of X chromosomes and decide if one needs to be inactivated, and if so which one. There is a region of the X chromosome called the X inactivation center which is enriched in long non-coding RNAs (lncRNAs). Lee explains how she and others showed that by sensing the ratio of two specific lncRNAs the cell can determine how many X chromosomes are present. Further studies showed that two different lncRNAs are responsible for randomly determining which X chromosome will be inactivated. Finally, she discusses the hypothesis that the allelic choice mechanism depends on a transient chromosomal pairing event that occurs at the beginning of the dosage compensation process.

Lee describes how X inactivation is nucleated and spreads across the X chromosome. The Xist lncRNA is known to be necessary and sufficient for X inactivation. Lee describes experiments that identified the factors that tether Xist to the X chromosome and showed how Xist spreads to cover the entire X chromosome. She then goes on to explain that Xist blocks transcription in three ways: 1) Xist recruits factors that repress transcription via epigenetic modification such as histone methylation 2) Xist repels factors that open chromatin preparing it for transcription and 3) Xist changes the 3 dimensional organization of chromosomes. Lee ends with a model of our current understanding of the complex but critical process of X chromosome inactivation.

Dr. Susanne Heck begins her talk by explaining why we might choose to use mass cytometry rather than other types of flow cytometry.  Traditional flow cytometry is typically limited to the detection of about a dozen parameters in one sample due to overlap between the emission spectra of fluorochromes used to label antibodies.  Mass cytometry, on the other hand, allows for the detection of up to 50 parameters in one sample because antibodies are labelled with metal isotopes and separated based on their mass. Heck goes on to explain which metal isotopes are typically used for mass cytometry and why, and she describes how a mass cytometer functions. She finishes by running through an example of using mass cytometry to perform functional phenotyping on human bone marrow cells.

The expansion of lungs for oxygen uptake is facilitated by lung surfactant. The groundbreaking discovery of this substance was made by Dr. John Clements. In this Discovery Talk, Clements details his scientific journey, touching on his early research, the resistance he encountered in the field, and the discovery of lung surfactant, which has saved millions of neonatal lives.

There are many processes and signals in cells that must be turned on and off, sometimes very quickly.  How is this done? One important way is via post-translational modification of proteins such as phosphorylation or dephosphorylation. In her first talk, Dr. Anne Bertolotti introduces us to protein phosphatases, the enzymes that remove phosphate from proteins and work in opposition to protein kinases. She gives a brief history of the early experiments that showed that phosphatases are vital to regulating the stability, localization and interactions of many proteins. Bertolotti also describes more recent work demonstrating that protein phosphatases are split enzymes with a catalytic subunit and a subunit that determines substrate specificity. This selective subunit makes phosphatases exquisitely specific and attractive targets for drug development.

Bertolotti’s lab has had a long time interest in understanding protein folding and the role of misfolded proteins in neurodegenerative disease. In her second talk, Bertolotti explains how her lab found that selectively inhibiting the dephosphorylation of eIF2⍺, a translation initiation factor, led to a reduction in protein synthesis. Decreasing protein synthesis allowed cells to “catch up” with the degradation of misfolded proteins that may accumulate as a result of cell stress. Her lab went on to show that a selective small molecule phosphatase inhibitor had therapeutic effects in a mouse model of Charcot-Marie-Tooth disease; a disease that results from the accumulation of misfolded protein in the ER.  This exciting result suggested that targeted inhibition of protein phosphatases may have therapeutic potential for neurodegenerative diseases.

Bertolotti describes a platform developed by her lab that has allowed them to rationally identify selective protein phosphatase inhibitors. Using this platform her lab identified a novel small molecule phosphatase inhibitor that blocks the accumulation of misfolded proteins in the cytosol or nucleus and showed the therapeutic effects of the molecule in a model of Huntington’s disease.

The immune system is responsible for fighting infection and disease. It is comprised of many specialized cell types, all which work together to keep people healthy. In this short video, Dr. Brittany Anderton introduces the cells of the immune system. She compares and contrasts innate and adaptive immunity, and lays out the molecular interactions required to activate each type of response.