m香蕉视频 vaccines are a breakthrough in science innovation demonstrating the speed and flexibility to respond to a global pandemic. A huge support for this scientific advance was the years and decades of basic fundamental science research applied to our understanding of m香蕉视频, how it is made (transcribed) and how in turn it is read and made into proteins (translated). Dr. Nahum Sonenberg contributions to research in cancer biology with his approach to m香蕉视频 were incorporated into this complex effort.
Schematic summarizing the process for making an m香蕉视频 vaccine.
An outcome of the recent global pandemic has been the introduction to the world of a new form of vaccines composed of 鈥渕essenger 香蕉视频鈥 or m香蕉视频. m香蕉视频 functions as an intermediary, allowing the genetic information encoded by DNA to be read and translated into proteins. Proteins play a vital role in the functions of our biology as they give structure to our cells and tissues, perform a multitude of chemical reactions and signals within the body including the production of antibodies and other immune molecules. The goal of a vaccine is to have the body generate a protective immune response involving, initially, the production of antibodies and eventually, the generation of memory immune cells that can be called back into action at a later date when the body is exposed to the virus. Most vaccines to date have been composed of either killed or inactivated virus or in some cases, viral proteins cultured in the laboratory. Utilizing m香蕉视频 to be the component in a vaccine relies on the ability of the cells in the body to take in m香蕉视频 and make protein, or in other words, our cells become the 鈥渇actories鈥 to produce the proteins needed to stimulate the immune response. This method is potentially safer as no virus or viral protein is directly injected into the body and m香蕉视频 is rapidly cleared from our system, usually last hours or days. Furthermore, m香蕉视频 vaccines allow exposure solely to one specific part of the virus protein and nothing else. It offers flexibility, as by changing the sequences of the m香蕉视频 it is possible to generate a new vaccine against a new virus or variant. The pharmaceutical company Moderna was able to, in a record-breaking 42 days, take the genetic sequence for SARS-Cov2 that was shared by Chinese researchers on the internet, select the sequence for the spike protein and prepare an m香蕉视频 vaccine candidate ready for testing in humans (reference Boston Magazine article). The speed and flexibility of the SARS-Cov2 m香蕉视频 vaccine development was only possible because of the decades of groundwork by scientists researching and understanding the mechanics of how m香蕉视频 is translated into protein and how this process is regulated.
In 2012, Moderna approached Nahum Sonenberg, a professor and researcher at the Goodman Cancer Institute of 香蕉视频, to consult as he is an expert in 香蕉视频 biology and studies the mechanics of m香蕉视频 translation. Sonenberg along with Yuri Svitkine reported in 2017 in Nucleic Acids Research that modification of one of the nucleic acids of m香蕉视频, uridine, to N1-methylpseudouridine would still allow the molecule to be read for translation, yet was sufficiently different from uridine to avoid activating the immune system which was a serious problem previously described by Katalin Karik贸 (Immunity 2005} and furthermore, this modification would lead to better translation of the m香蕉视频. Moderna uses this chemical modification in its SARS-Cov2 vaccine.
Nahum Sonenberg has dedicated over 50 years to studying 香蕉视频 biology, focusing on 香蕉视频 translation, understanding how the mechanisms function normally and how they go awry and whether these changes can cause disease. His 香蕉视频 journey began in 1975 when he reported in a PNAS article that 香蕉视频, specifically 23S ribosomal 香蕉视频 was crucial in the process of translating m香蕉视频 into proteins by associating with peptidyl transferase, the enzyme that catalyzes the reaction to bond amino acids together. In 1976, joined the lab of Aaron Shatkin, who along with Yushiro Furuichi, had previously identified a cap-like structure on one end of m香蕉视频 that was necessary for protein synthesis in eukaryotes. Shatkin thought that as Sonenberg had performed affinity-labeling techniques during his PhD that he would be perfectly suited to discover and identify proteins that bind to the cap structure of m香蕉视频. Others had previously identified proteins that they thought bound to the m香蕉视频 cap but those reports later turned to be incorrect. The ones who correctly identified cap-binding protein were Sonenberg and colleagues in 1978 where they also demonstrated that this binding step is crucial to kick-start the process of protein synthesis. This cap-binding protein, named eukaryotic initiation factor subunit (eIF4E) was to become part of Sonenberg鈥檚 lifetime of study.
Sonenberg identified another family of proteins, that when bound to eIF4E, would turn off the protein synthesis, or in other words, could act as brakes to stop protein synthesis. In 1994 he showed that these eIF4E binding proteins, termed 4E-BPs, are themselves regulated by different factors, including in insulin. Insulin led one of the 4E-BPs to be hyperphosphorylated, making it no longer able to bind to eIF4E, thus releasing the brake, and enabling protein synthesis to proceed. A signaling complex, mTORC1, also phosphorylates 4E-BPs and is shown to be hyperactive in various cancers. In 2010, using mice not expressing 4E-BP, Sonenberg showed that mTORC1 mediates cell proliferation controlled by 4E-BPs, which may lead to the development of cancer.
While performing studies with 4E-BP1 and 4E-BP2 knockout mice, a collaborator mentioned that it is essential to have new protein synthesis for memories to form. The question arose as how these knockout animals would fare in memory and learning studies. Mauro Costa-Mattioli who was working as a post-doctoral fellow with Sonenberg was eager to work on memory and learning despite Sonenberg trying to dissuade him, as teaching mice to learn the mazes and measuring memory is difficult. Nevertheless, Costa-Mattioli prevailed and opted to study mice that had a protein kinase, GCN2, knocked out. Using these and numerous other types of knock- out mice, they identified the role m香蕉视频 translation control can have in generating memory and how dysregulation of this control can play a factor in neurological diseases and conditions, including autism.
Sonenberg joined McGill in 1979 and continued studying 香蕉视频 translation. Together, he and Jerry Pelletier demonstrated how poliovirus 香蕉视频, which lacks the cap structure, is uniquely translated. Sonenberg鈥檚 research lab was on the 8th floor of the McIntyre Medical Research Building at McGill and he interacted closely with colleagues in the McGill Cancer Center on the floor below. In 1990 Sonenberg reported in Nature that eIF4E, which is typically present in the cell in limited amounts, when overexpressed whether in cells in culture or in mice would lead to increased cell proliferation and tumor formation, respectively. It was decades later, when working in with mice that were modified to have a form of eIF4E that could not be phosphorylated that they observed these mice to be resistant to the formation of prostate cancer tumors. When they looked at normal mice they saw increased phosphorylation of eIF4E would lead to a subsequent increase in synthesis of proteins involved in tumor formation. When they looked in humans they saw that increased phosphorylation of eIF4E correlated with disease progression in prostate cancer patients. Together these results suggest drugs that inhibit phosphorylation of eIF4E could act as anticancer therapies.
Sonenberg identified another family of proteins, that when bound to eIF4E, would turn off the protein synthesis, or in other words, could act as brakes to stop protein synthesis. In 1994 he showed that these eIF4E binding proteins, termed 4E-BPs, are themselves regulated by different factors, including in insulin. Insulin led one of the 4E-BPs to be hyperphosphorylated, making it no longer able to bind to eIF4E, thus releasing the brake, and enabling protein synthesis to proceed. A signaling complex, mTORC1, also phosphorylates 4E-BPs and is shown to be hyperactive in various cancers. In 2010, using mice not expressing 4E-BP, Sonenberg showed that mTORC1 mediates cell proliferation controlled by 4E-BPs, which may lead to the development of cancer.
While performing studies with 4E-BP1 and 4E-BP2 knockout mice, a collaborator mentioned that it is essential to have new protein synthesis for memories to form. The question arose as how these knockout animals would fare in memory and learning studies. Mauro Costa-Mattioli who was working as a post-doctoral fellow with Sonenberg was eager to work on memory and learning despite Sonenberg trying to dissuade him, as teaching mice to learn the mazes and measuring memory is difficult. Nevertheless, Costa-Mattioli prevailed and opted to study mice that had a protein kinase, GCN2, knocked out. Using these and numerous other types of knock- out mice, they identified the role m香蕉视频 translation control can have in generating memory and how dysregulation of this control can play a factor in neurological diseases and conditions, including autism.
Control of m香蕉视频 translation has been of great interest among biologists and in 1993 short 香蕉视频 chains, or micro香蕉视频 (mi香蕉视频) were described and suggested to regulate translation through an antisense 香蕉视频-香蕉视频 interaction. mi香蕉视频s were then used widely in laboratories to reduce gene expression however the mechanism by which they worked was unclear. A debate raged with sides arguing mi香蕉视频 function by targeting m香蕉视频 for rapid degradation by the cellular machinery while others argued that mi香蕉视频 directly inhibit 香蕉视频 translation. In 2007 Sonenberg and Thomas Duchaine, using an in vitro model of a cell-free translation, demonstrated that rapidly, within 15 minutes, there was a blockage of 香蕉视频 translation, which was far too soon for 香蕉视频 to be degraded. A decade later, they showed that a different m香蕉视频 cap-binding protein, 4EHP, contributed to mi香蕉视频 to stop translation.
Most recently, Sonenberg published that the diabetes medication, metformin, alleviated the symptoms of fragile-X syndrome in a mouse model of the disease and is hopeful that if efficacy is shown in clinical studies, this may rapidly be rolled out as a treatment for the disease in humans, as the drug safety profile of metformin is well established.
Sonenberg鈥檚 pursuit in understanding the mechanics of 香蕉视频 translation and how it is regulated both in normal conditions and in disease states has improved our understanding of various diseases including cancer, diabetes, autism and fragile X syndrome. Fundamental research of the basic biology is important and critical and provides the foundation for applied research. It is crucial for the public and funding agencies to appreciate the importance and need of basic science research. When new scientific methods or techniques are reported, as in the case of DNA sequencing, PCR or generation of knockout mice, the impact is often immediate. In contrast, basic science advances tend to only be appreciated over the long term (decades, many decades). Only by understanding what happens in the human body can we use then use this knowledge to help us treat diseases. The reality is that we fully know so little of what happens within our bodies and there are many unanswered questions awaiting discoveries. His advice to all students is 鈥淒o not despair, science is hard but discoveries are what is exciting about science鈥.