iBiology Videos

In her third lecture, Zoghbi explores possible therapies for MECP2 disorders. First, using Deep Brain Stimulation (DBS), Zoghbi’s team together with collaborator Dr. Jianrong Tang were able to rescue learning and memory deficits, enhance neurogenesis, correct abnormal neural network activity, and improve MeCP2-linked gene expression changes in a mouse model of Rett Syndrome. Then, she discusses two approaches to normalize the MeCP2 protein in MECP2 duplication mice: by deleting the duplicated MECP2 gene in the genome, or by decreasing MECP2 mRNA levels using antisense-oligonucleotides. Even though these two approaches seem to rescue developmental issues caused by MECP2 duplication, titrating MeCP2 levels is required in order to avoid Rett-like symptoms caused by lowering the protein too much.

In her second lecture, Zoghbi explains how MeCP2 molecularly modulates neuronal function. Their studies uncovered a critical link between cytosine methylation, MeCP2, and the methylating enzyme Dnmt3a, in Rett Syndrome. They hypothesized that MeCP2 partially causes Rett-Syndrome symptoms by failure of reading methylated DNA marked by Dnmt3 and indeed showed that Dnmt3-dependent mCH plays a central role in Rett pathogenesis.

Dr. Huda Zoghbi’s work has provided insight into Autism Spectrum Disorders (ASD) by focusing on Rett Syndrome, a postnatal progressive neurological disorder. By studying the genetics of Rett Syndrome, her group made the seminal discovery of X-linked Methyl CpG-binding protein 2 (MECP2) as the gene that causes Rett Syndrome. Zoghbi’s group showed that the severity of the disease was highly dependent on the amount of functional MeCP2 protein expressed. Females, who carry one normal and mutant MECP2 allele typically suffer from Rett syndrome, but the amount of functional protein is influenced by X-chromosome inactivation, and girls with more cells expressing normal allele have milder features. Surprisingly, they also showed that duplications spanning MECP2 can cause a Rett-like progressive neurological disease, highlighting the importance of MeCP2 levels for neural functions. Zoghbi describes how these findings have spurred new research into how MeCP2 affects postnatal development and brain function.

Witkin provides a historical perspective on how working at Cold Spring Harbor (CSH) shaped her scientific career and led to the discovery of the SOS DNA damage response in bacteria. At CSH she worked with the pioneers of bacterial genetics, at a time when there was a major discovery every other week. As a PhD student Witkin observed that some bacteria were able to survive high doses of UV radiation. She speculated that these bacteria may have a mechanism to repair DNA making them UV resistant. These revolutionary ideas gave birth to the discovery that cells have a mechanism to repair DNA damage, the SOS response.

Dr. Chris Voigt explains that, for synthetic biologists to engineer cells that can make complex chemicals or perform complex functions, they must be able to tell the cell which genes to turn on and at what time. To do this they build genetic circuits composed of a series of gates that respond to a specific input with a specific output. Voigt’s lab has developed a library of gates that can be interconnected, will function robustly and will not interfere with each other. In addition, they have developed software that lets users arrange the gates to form a circuit of their choice. The software provides DNA sequence encoding the genetic circuits, and the DNA can be synthesized and inserted into a cell. Voigt’s lab has successfully built and tested genetic circuits in many cell types to make many products.

Vale explains how doing science often follows a winding path with unexpected, sometimes wonderful surprises, and uses his own story to illustrate his point. When Vale was a graduate student, he initially hoped to show that myosin was involved in axonal transport, but ended up discovering a new molecule which he called kinesin.

As the COVID-19 pandemic escalated in the beginning of 2020, there was a need for the rapid dissemination of scientific information to understand everything from how the virus spreads, to how it affects the human body, to how the disease can be treated and prevented. Jessica Polka, Executive Director of ASAPbio, explains that, for this reason, the pandemic has inspired an increasing number of scientists to post their research papers on preprint servers. Publishing papers in traditional journals with formal peer review can take a lot of time. Posting manuscripts on preprint servers, on the other hand, can happen quite fast. But, considering that preprints do not undergo formal peer review before they are posted, is this prudent? Dr. Polka talks about how preprints experience their own crowd-sourced, informal peer review process through public commentary on social media and other venues by scientists and other experts, and this discourse can actually improve the quality of the paper over time. A major caveat of preprints is the potential for the media and the public, who may not be aware of the provisional nature of preprints, to disseminate erroneous or inaccurate information, and so, this requires proper education and training on what preprints are and how to interpret them.

Dr. Jan van der Meer begins by giving an introduction to synthetic biology. Through this introduction to synthetic biology, he explains that DNA and protein “parts” can be put together to form biological circuits in a manner analogous to making electrical circuits from transformers, capacitors, and the like. These circuits can be designed for many applications in health and agriculture etc. van der Meer concludes his talk by describing work from his lab to engineer biosensor bacteria that can measure toxic compounds in the environment. For example, a simple system of a bacterial cell, which glows in the presence of arsenic, can be used to test drinking water in Bangladesh for high levels of arsenic.

In the cytoplasm of cells, thousands of tightly packed molecules and structures execute the numerous processes necessary to maintain life. Although there are many ways to study cellular processes, one of the simplest ways to understand the different parts of a cell is to visualize them. Dr. Sven Truckenbrodt sought to better understand the machinery of the neuronal synapse using fluorescence microscopy, yet he was limited by the physical properties of light. To circumvent the 250-nm resolution limit imposed by the photophysics of light waves, Truckenbrodt developed X10 expansion microscopy, based on the original concept of expansion microscopy invented in the Boyden lab. By uniformly expanding the volume of tissue by a thousand-fold using synthetic polymers (the same as those found in baby diapers!), this approach increases the distance between closely packed proteins, allowing them to be visualized with fluorescence microscopy. Truckenbrodt shares the story of the first time he used X10 expansion microscopy to clearly image synaptic vesicles, after studying them for years as a neuroscientist! He describes how he used X10 microscopy to characterize the precise localization of synaptic and cytoskeletal proteins that previously could not be visualized in detail. Truckenbrodt ends his talk by sharing how the X10 approach has been used by other research groups and encourages his viewers to consider applying this method in their own research to make new discoveries.

In his last lecture, Singer continues the story of the life and death of RNA. His lab has developed several more fluorescence microscopy techniques that let them study, in real time, the translation and degradation of mRNA. These techniques allow them to track when and where translation begins, how quickly a ribosome binds to a mRNA once it has reached its destination, how long the ribosome stays bound and how rapidly it adds amino acids to a growing protein chain.  In addition, these techniques can be used to unveil the dynamics of RNA degradation. In an interesting twist, it turns out that for mRNAs that must be degraded during the cell cycle, their fate is decided at the time of their birth.