Making Sense of it all

By Edwin J. Weeber, Ph.D.,

Professor, Department of Molecular  Pharmacology and Physiology, Chief Scientific Officer, USF Health Byrd Alzheimer’s Institute Director, Neurobiology of Learning and  Memory Laboratory,  University of South Florida Health’s Morsani  College of MedicineMany of you reading this magazine are more immersed in medical science and scientific discovery then most of the population. With a focused eye on the latest work being performed in the field of Angelman syndrome, there are reports, papers, talks and posts that seem to be in constant conflict. It’s important for you all to know that this is actually a good thing! Rarely are there “eureka” (I’ve found it) moments in science. Instead we follow our instincts and often let the results of the science lead us down the path of discovery. Sometimes, even when discoveries are made they are not immediately accepted in the broader field. With this in mind, I have a favorite story that I often tell to new graduate students about two very famous scientists: Camillo Golgi and Santiago Ramon Y Cajal.

We need to go back in time to the 1800s when the Reticular Theory predominated science. The Reticular Theory maintained that the nervous system was a continuously connected network of fibers or a “reticulum”. Cells were known at the time as the basic unit of life, but the human brain and that of other mammals at a gross (really gross) level looked like just a bunch of mush. Camillo Golgi, a neuroanatomist, was a strong proponent of the Reticulum Theory and when Cajal suggested that neurons were discrit cells that made specific connections to other neurons (The Neuronal Doctrine) Golgi publically ridiculed such a thought. Cajal was undaunted. The complexity of the brain and subsequent complexity of the human cognitive strongly suggested that complex interactions of specific types of neurons were needed. In other words, neurons needed to be independent units and allow signaling with directionally.

In order to convince others of the Neuron Doctrine he needed to show that different types of neurons existed and that these neurons connect to other neurons at distinct places (synapses). Golgi had developed a unique staining method for looking at neurons. This basic method could impregnate cells to see their structures under a microscope. Today this is referred to as Golgi staining and is used today in many laboratories, including my own. Cajal used Golgi’s new technique to show these synaptic connections and garner support from other scientists that the Neuronal Doctrine should replace the Reticular Theory. Golgi, despite this evidence, never gave in and continued support the Reticular Theory. Santiago Ramon Y Cajal was awarded the 1906 Nobel Prize for Medicine along with Camillo Golgi for the development of the silver nitrate impregnation technique (Golgi Staining).  Golgi’s 1906 acceptance speech was a well worded and polite attack on the Neuron Doctrine. Cajal’s speech was a little more magnanimous and he acknowledged that without Golgi’s technique the Neuron Doctrine would not have gained support.

The reason I tell the story to burgeoning new researchers is to let them know that science is not mathematics. There is often no correct answer at the end of a single experiment, especially for the really big, complicated questions. The culmination of many types of scientific work and contributions of many researchers is what finally addresses all the conflicts, allowing for the best possible final product. This takes time and countless hours in the laboratory, discussing conflicting data from others and sometimes looking beyond the single graph of data or talk at a conference. It took time and data for the Reticular Theory and eventually the Neuronal Doctrine. So it goes with Angelman syndrome research; it is evolving. In the next issue we can discuss the accumulation of recent papers and published research and what it means for the Angelman Doctrine. On a side note, Cajal and Golgi remained friends throughout their careers despite being on opposite sides of the Neuronal Doctrine.

 

Article of interest: 

Title: Topoisomerases facilitate transcription of long genes linked to autism

Authors: Ian F. King, Chandri N. Yandava, Angela M. Mabb, Jack S. Hsiao, Hsien-Sung Huang, Brandon L. Pearson, J. Mauro Calabrese, Joshua Starmer, Joel S. Parker, Terry Magnuson, Stormy J. Chamberlain, Benjamin D. Philpot & Mark J. Zylka

Abstract: Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.

Topoisomerase inhibitors are being considered as a potential therapeutic for AS. This article exemplifies the non-specific actions of topoisomerase inhibitors on many genes and suggests a link between chemicals that may act on topoisomerases and Autism.