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To the untrained ear, “protein space” sounds like a cheeky name for a bodybuilding gym. For the evolutionary biologist, however, it’s a place to spend a career. Coined by the pioneering theoretical biologist John Maynard Smith in 1970, the term is a metaphor for the computational landscape where scientists can survey every possible sequence of a particular protein, trace its historic path of evolution, and even predict where natural selection might locate its next biophysically viable mutation — in other words, how the protein will adapt and express itself in real life.  Representations and applications of John Maynard Smith’s “Protein Space.” “A” shows the simplest path through a computational space to solve a word puzzle, where only one letter can be changed at a time to get from “word” to “gene.” “B” shows the same concept, but applies it to mutations in a real protein sequence. Graphic: Genetics, April 2020 Right now, this protein “mapping” is playing a crucial role in the quest to understand SARS-CoV-2, the virus that causes Covid-19. Researchers around the planet are studying the protein spaces of the deadly virus so that vaccines and therapies can effectively fight it. Among them is Tyler Starr, a postdoctoral researcher at the Fred Hutchinson Cancer Research Center. In a paper published in June, Starr and his colleagues did a mapping experiment to determine how mutations in the “key” part of the virus (aka the “receptor binding domain”) could affect its ability to lock into the “keyhole” (aka ACE2 receptors) of human cells. They located sequences that significantly improved that binding, but those sequences hadn't been detected in nature yet. But now they're infecting humans. One of those mutations to the RBD, known as N501Y, has come to scientists’ attention due to its repeated emergence in several global lineages such as the "B.1.1.7" lineage first identified in the UK. "Now it’s only rising in frequency,” said Starr. He and other scientists aren’t sure if that’s due to adaptive pressures on the virus created by immunity, or due to other changes in its structure. But these are questions that protein mapping can help with: Scientists can think about mutating proteins traversing a “fitness landscape” that is shaped by shifting evolutionary pressures. They can build models to try and see where it’s going next, and to try to fend it off before it gets there. That’s another thing Starr is working on: His latest paper maps possible future mutations in a part of the virus’s protein structure that could make it less receptive to antibody treatments. That way, future antibody therapies could be strengthened against those potential mutations, helping humanity finally map its way out of Covid-19.  Starr's latest research includes what he calls "maps" of mutations that escape binding by antibody treatments, where the X axes show different protein sequences and Y axes show how those sequences impact binding. The color scale refers to effects on ACE2 binding. Graphic: Science, January 2021 Frontline workers: Let us map with you Walee Phiriyaphongsak/Bloomberg CityLab Walee Phiriyaphongsak/Bloomberg CityLab As part of our ongoing Covid-19 mapping project, CityLab wants to document and include the experiences of people who work in healthcare, food service, transportation, education, manufacturing, processing or any other frontline field. If you’re interested in sharing your pandemic experience and working with an artist to turn it into a map, please send an email to maplab@bloomberg.net with your location, occupation and some ideas about what you’d like to visualize. A CityLab journalist will be in touch. Map links
Stay healthy, stay safe. Sign up for MapLab here.Laura Bliss |
