iBiology Videos

In his third lecture, Gadek outlines Lifitegrast clinical trials, from Phase 1 to Phase 3, and presents evidence of Lifitegrast’s safety profile in normal individuals as well as the efficacy of the drug in treating dry eye syndrome. Lifitegrast’s story shows the different layers of drug development and the steps that companies go through to take a drug from the laboratory to the patient’s bedside and ultimately to the market.

In his second lecture, Gadek reviews the molecular mechanism of dry eye syndrome, focusing on the role of inflammation and T-cells in this disorder.  By analyzing clinical trial data from other drugs developed to treat dry eye, Gadek and colleagues confirmed the importance of LFA-1 as a possible target.  LFA-1 is a surface protein on T-cells that binds to ICAM-1 on antigen presenting cells, T-cells,  and epithelial cells and causes inflammation.  Gadek and his colleagues developed Lifitegrast, a small molecule that serves as an ICAM-1 mimetic. By binding to LFA-1 on T-cells, Lifitegrast inhibits the binding of ICAM-1 and therefore inhibits the inflammation associated with dry eye syndrome.

Using the company he co-founded, SARcode, as an example, Dr. Tom Gadek tells us how one converts a novel idea into a successful company.  He walks us through the discovery of Lifitegrast to treat dry eye syndrome, the founding of SARcode in 2006, and the subsequent clinical trials.  In his first talk, Gadek highlights the financial challenges a company faces during its development and stresses the importance of presenting the company as a valuable investment to venture capital groups.  While describing the process of developing a company, Gadek offers three main points of advice: surround yourself with people that work well with you, get good lawyers, and always do quality science and publish your results.

About half of the cells in an adult heart are cardiac myocytes, or muscle cells, and about half are cardiac fibroblasts or support cells.  Following a heart attack, muscle is lost and fibroblasts form scar tissue.  In his second talk, Srivastava asks whether our understanding of embryonic heart development can be used to reprogram fibroblasts to myocytes to repair damaged adult hearts. His lab showed that introducing the genes for 3 transcription factors important for embryonic cardiac development resulted in an increase in the number of myocytes in a mouse heart after an induced heart attack. Similar results were obtained in vivo in pigs and in vitro in human cells suggesting that in vivo cellular reprogramming by gene therapy has broad implications for organ regeneration.

During embryogenesis, the heart needs to form a specific three-dimensional shape or a child will be born with a defective heart. Srivastava and his colleagues hope that by better understanding the molecular pathways involved in normal heart development, it will possible to improve treatments for both congenital and adult onset heart disease. In his first talk, Srivastava describes studies from his lab and others which use animal models and induced pluripotent stem cells to elucidate many of the gene networks that determine cardiac cell fate. iPS cells have been particularly important for identifying a mutation in the human transcription factor GATA4.  By understanding the importance of GATA4 during heart development, it has been possible to develop a model that explains how cardiac specific genes can be activated while genes for other cell types are repressed.

By studying families with sleep/wake disorders, Fu and Ptáček have shown that mutations that cause changes in the phosphorylation or acylation of the PER2 protein are responsible for regulating circadian rhythms.

In Part 2 of the talk, Dr. Fu explains that studies of families with sleep disorders have shown that post-translational modifications of the PER2 protein are involved in regulating circadian rhythms. Casein kinase 1 phosphorylates PER2 and mutations in either CK1 or specific serine residues in PER2 result in an advanced sleep phase phenotype. O-GlcNAcylation of PER2 also participates in regulating circadian rhythms because O-GlcNAcylation blocks the sites usually phosphorylated by CK1.

By studying families with sleep/wake disorders, Fu and Ptáček have shown that mutations that cause changes in the phosphorylation or acylation of the PER2 protein are responsible for regulating circadian rhythms.

Ptáček introduces the circadian clock and its relationship to sleep.  He describes different sleep-wake behaviors including people who go to sleep and awaken exceptionally early or late. By studying families with an advanced sleep phase (ASP) phenotype, he and his colleagues showed that these individuals had a shortened circadian period. Further studies of families with similar sleep-wake behaviors have identified a number of mutations responsible for circadian rhythm regulation.

In the second video, Dr. Duncan explains that the inner segment of photoreceptor cells, where proteins are made, and the outer segment, where light is transduced into a chemical signal, are joined by connecting cilia. Mutations in proteins that localize to the connecting cilia can lead to photoreceptor cell death and vision loss.  In a number of syndromic diseases, such as Bardet-Biedl Syndrome, retinal degeneration is just one of several symptoms all of which are caused by mutations in cilia throughout the body.  By identifying specific gene mutations causing retinal degeneration, Duncan hopes that better treatments for patients with these syndromes will be developed.

Cilia and flagella are complex, but highly conserved, structures found on most cells of the human body. Mutations in proteins localized to cilia can cause a collection of human diseases including renal failure and retinal degeneration. Dr. Marshall begins with an overview of the complex internal structure of cilia and flagella and the machinery, called intraflagellar transport (IFT), required to build and maintain these structures. Mutations in motile cilia were known to cause several human diseases but it wasn’t until scientists began studying IFT in the green algae Chlamydomonas, that the key role of non-motile cilia in human health and development was recognized. Marshall describes how mutations in cilia and basal bodies can cause human diseases as different as renal failure and retinal degeneration.

In the second lecture, Dr. Matthew State overviews the hunt for genes associated with autism and explains how studying de-novo rare mutations in the germline has advanced the understanding of the genetics of autism spectrum disorder (ASD). Studying a cohort of families with one affected individual and one unaffected sibling, they were able to map multiple genes involved in ASD. Because of the complexity of the developing brain, the same gene could act upon different regions of the brain at different times during development. Therefore, after identifying genes associated with ASD, they characterized the region and time during development where these genes are expressed and more likely to have an effect that is associated with ASD.