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Type Name Latest commit message Commit time data we be writing pdbs Apr 2, 2020 proteins denatured Apr 3, 2020 vaccine TOC Jan 2, 2021 .gitignore data and helpers Mar 23, 2020 README.md Update README.md Jan 11, 2021 corona.py bug fix Mar 31, 2020 download_sequences.py add sars Mar 23, 2020 fold.py fix solvent Apr 3, 2020 lib.py straight line Apr 3, 2020 opt.py it's RNA, not DNA Jan 3, 2021 View code Reverse engineering the coronavirus (SARS-CoV-2) Background Biology vs. software Progress Downloading the SARS-CoV-2 genome Translating RNA to proteins Annotating functions Folding proteins Work to be done Open questions Testing How tests work Homemade test? Possible treatments and prophylactics Hydroxychloroquine + zinc RdRP inhibitors Dexamethasone Lopinavir-Ritonavir (AIDS cocktail) Resources Coronavirus-related publications Biology Bioinformatics Epidemic modeling Antibodies Masks Vaccines Genome studies (what genes = bad covid) DNA Synthesis README.md Reverse engineering the coronavirus (SARS-CoV-2) Start here: corona.py Background This project applies techniques from reverse engineering to understand the SARS-CoV-2 virus. The goal here is simply to build an understanding of the virus from first principles. Biology vs. software Biological systems are fundamentally information processing systems. While not a perfect analogy, software provides a useful framework for thinking about biology. The table below provides a rough outline of this analogy. Biology Software Notes nucleotide byte genome bytecode translation disassembly 3 byte wide instruction set with arbitrary " reading frames" protein function a polyprotein is a function with multiple pieces protein secondary basic blocks 80% accuracy in prediction structure protein This seems like the hard one to predict: tertiary https://journals.plos.org/plosone/article?id= structure 10.1371/journal.pone.0205819 quaternary compiled https://en.wikipedia.org/wiki/ structure function with Protein%E2%80%93protein_interaction_prediction inlining gene library bacteria are statically linked, viruses are dynamically linked transcription loading protein library structure identification prediction genome static analysis analysis molecular dynamics dynamic Simulation doesn't seem to work yet. simulations analysis Constrained by tooling and compute. of protein folding We are reverse engineering a CAD format. Runs no equivalent execution more like FPGA code, all at once. No serial execution. (What are the FPGA reverse engineering tools?) Progress Downloading the SARS-CoV-2 genome GenBank is the NIH genetic sequence database, an annotated collection of all publicly available DNA and RNA sequences. The SARS-CoV-2 sequences available in GenBank have been downloaded in download_sequences.py. Translating RNA to proteins lib.py contains a function translate that converts an RNA sequence to a chain of amino acids. This function is used in corona.py. Annotating functions The translate function is used in corona.py to identify and annotate functions for all proteins encoded by the genome. Folding proteins The OpenMM toolkit is used for molecular simulation of protein folding in fold.py. Work to be done * Automatic extraction of genes from different coronaviruses * Good multisequence compare tool * Molecular dynamics? * Secondary Structure prediction on orf1a? Open questions * How is orf1ab cleaved into polypeptides? Can we predict this from the sequence? * How do the researchers know (guess?) where orf1ab cleaves? + nsp3 and nsp5 do it -- https://www.pnas.org/content/pnas/103/ 15/5717.full.pdf * Which protein is the immune system responding to? + "spike" and "nucleocapsid" -- http://www.cmi.ustc.edu.cn/1/3/ 193.pdf + Are some people already immune from exposure to other coronavirus? * Find the "furin cleavage site" in the "spike glycoprotein" + It might be at the "PRRA" -- https://www.sciencedirect.com/ science/article/pii/S0166354220300528 + Use ProP or PiTou to predict? -- https://en.wikipedia.org/ wiki/Furin * How similar are the other coronaviruses? (causes colds, not either SARS or MERS) + alpha o https://en.wikipedia.org/wiki/Human_coronavirus_229E (simpler, though targets APN) o https://en.wikipedia.org/wiki/Human_coronavirus_NL63 (targets ACE2!) # https://www.ncbi.nlm.nih.gov/nuccore/MG772808 + beta o https://en.wikipedia.org/wiki/Human_coronavirus_OC43 (targets Neu5Ac) # https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095096/ pdf/JIDMM17330.pdf # Specifically, how similar is the N protein OC43, SARS v1, and SARS v2? o https://en.wikipedia.org/wiki/Human_coronavirus_HKU1 (targets Neu5Ac) o MERS-CoV o SARS-CoV o SARS-CoV-2 * What adds the phosphate group to the N protein? Kinase? Testing How tests work * All based on https://en.wikipedia.org/wiki/ Reverse_transcription_polymerase_chain_reaction * USA -- https://www.fda.gov/media/134922/download + selected from regions of the virus nucleocapsid (N) gene + 28286---28308--28332---28358 + 29163---29187--29210---29230 + https://biosearchtech.a.bigcontent.io/v1/static/ coa_KIT-NCOV-PP1-1000_Lot-No-143503 * South Korea -- http://www.kogene.co.kr/eng/about_us/news/ listbody.php?h_gcode=board&h_code=7&po_no=288 + E gene detection (same for all coronavirus) + specific RdRp detection Homemade test? * Isolation of viral RNA (no matter what) + https://www.qiagen.com/us/products/ diagnostics-and-clinical-research/sample-processing/ qiaamp-viral-rna-mini-kit/#orderinginformation * Primers and probes (to detect SARS-CoV-2) + https://www.biosearchtech.com/products/pcr-kits-and-reagents/ pathogen-detection/ 2019-ncov-cdc-probe-and-primer-kit-for-sars-cov-2 + Wouldn't need if using a nanopore sequencer (nanopore MinION) * RT-qPCR Master Mix (to PCR) + https://www.thermofisher.com/order/catalog/product/A15300#/ A15300 + Probably wouldn't need if using a nanopore sequencer * All in one? + https://www.chaibio.com/coronavirus + Open qPCR, understand https://www.chaibio.com/openqpcr + FAM and HEX fluorophores? Possible treatments and prophylactics [?][?] Disclaimer: The information in this repository is for informational purposes only. It is not medical advice. Hydroxychloroquine + zinc * Zinc blocks RdRp * https://jvi.asm.org/content/91/21/e00754-17 -- how similar is Hep E RdRp? * https://www.ncbi.nlm.nih.gov/pubmed/21079686 * Chloroquine Is a Zinc Ionophore (allows zinc into the cell) * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/ * Without zinc (seems ineffective) + https://www.recoverytrial.net/files/ hcq-recovery-statement-050620-final-002.pdf (where is study?) * With zinc + https://www.infezmed.it/media/journal/Vol_28_2_2020_9.pdf + https://www.sciencedirect.com/science/article/pii/ S0306987720306435 + No results yet: https://www.clinicaltrials.gov/ct2/show/ NCT04377646 RdRP inhibitors * Favipiravir (prodrug for favipiravir-RTP) * Adenosine Analog + Remdesivir (prodrug for GS-441524) o https://www.nejm.org/doi/pdf/10.1056/NEJMoa2007764? articleTools=true + Galidesivir Dexamethasone * corticosteroid = anti-inflammatory + immunosuppressant * https://www.medrxiv.org/content/10.1101/ 2020.06.22.20137273v1.full.pdf * Effects in late stage (blocking immune response?) Lopinavir-Ritonavir (AIDS cocktail) * Both drugs are protease inhibitors * Wouldn't expect it to work, don't think covid has protease * No effect: https://www.recoverytrial.net/files/ lopinavir-ritonavir-recovery-statement-29062020_final.pdf Resources Coronavirus-related publications * Chapter 4 - Coronavirus Pathogenesis -- https:// www.sciencedirect.com/science/article/pii/B9780123858856000092 * https://www.futuremedicine.com/doi/pdf/10.2217/fvl-2018-0008 * https://www.sciencedirect.com/science/article/pii/ S2095177920302045 * http://korkinlab.org/wuhan * https://github.com/mattroconnor/deep_learning_coronavirus_cure Biology * textbooks + Molecular Biology of the Cell * classes + better tests - https://ocw.mit.edu/courses/biology/ 7-012-introduction-to-biology-fall-2004/index.htm + suspected better lectures - https://ocw.mit.edu/courses/ biology/7-014-introductory-biology-spring-2005/index.htm + alternative lectures - https://youtube.com/playlist?list= PLGhmZX2NKiNldpyRUBBEzNoWL0Cso1jip + basics - https://www.khanacademy.org/science/biology Bioinformatics * Nextstrain + https://nextstrain.org/ncov + https://github.com/nextstrain/ncov + https://github.com/nextstrain/augur * https://biopython.org/ * https://github.com/cogent3/cogent3 * https://www.reddit.com/r/bioinformatics/comments/191ykr/ resources_for_learning_bioinformatics/ * https://en.wikipedia.org/wiki/Bioinformatics Epidemic modeling * https://gabgoh.github.io/COVID/index.html * http://epidemicforecasting.org Antibodies * https://www.medrxiv.org/content/10.1101/ 2020.07.09.20148429v1.full.pdf * https://www.medrxiv.org/content/10.1101/ 2020.05.11.20086439v2.full.pdf Masks * Looking for large controlled studies measuring infection rate with/without wearing mask * https://bmjopen.bmj.com/content/bmjopen/5/4/e006577.full.pdf -- cloth masks bad surgical masks nothing * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2662657/pdf/ 08-1167_finalRCME.pdf -- unclear, low adherence * https://sci-hub.tw/10.1001/archpedi.1987.04460060111049 -- masks + goggles help, unclear on mask type * https://onlinelibrary.wiley.com/doi/epdf/10.1111/ j.1750-2659.2011.00198.X -- N95 ~2x more effective than medical masks * https://jamanetwork.com/journals/jama/article-abstract/184819 -- N95 and surgical similar in effectiveness Vaccines * https://en.wikipedia.org/wiki/COVID-19_vaccine * https://www.nytimes.com/interactive/2020/science/ coronavirus-vaccine-tracker.html * generic vaccine types -- https://www.niaid.nih.gov/research/ vaccine-types * Nucleic Acid Vaccines (none are currently used) + Use mRNA to produce viral proteins o "It's a very unique way of making a vaccine and, so far, no (such) vaccine has been licenced for infectious disease" o Moderna, mRNA-1273 -- https://clinicaltrials.gov/ct2/show /NCT04283461 o https://www.biorxiv.org/content/10.1101/ 2020.04.22.055608v1.full.pdf o https://www.medrxiv.org/content/10.1101/ 2020.06.30.20142570v1.full.pdf + DNA vaccine o "No DNA vaccines have been approved for human use in the United States" o Based on injecting DNA (plasmid) that expresses the spike protein o https://siasky.net/ bACLKGmcmX4NCp47WwOOJf0lU666VLeT5HRWpWVtqZPjEA + Viral Vector Vaccines o "There are no viral vector vaccines currently on market for use in humans." o adenovirus vector, AZD1222 o recombinant adenovirus type 5 vector, Ad5-nCoV * Protein-Based Vaccines (subunit vaccines?) * Whole-Virus Vaccines (inactivated vs live-attenuated) + Like old vaccines (live attenuated?) + In phase 3 already, Sinopharm = 15,000 people * Nanoparticle vaccine? + https://www.ipd.uw.edu/2019/03/ ipds-first-nanoparticle-vaccine/ * Reverse Engineering + https://berthub.eu/articles/posts/ reverse-engineering-source-code-of-the-biontech-pfizer-vaccine / + https://berthub.eu/articles/posts/ part-2-reverse-engineering-source-code-of-the-biontech-pfizer-vaccine / Genome studies (what genes = bad covid) * https://www.nejm.org/doi/full/10.1056/NEJMoa2020283?source= nejmtwitter&medium=organic-social DNA Synthesis * Produce "oligos" of around 170-200 bp + "Phosphoramidite chemistry" -- it's a chemical process + Size limited by 0.99^n -> 13% yield on 200bp if the process is 99% good + Column based / Array based + https://www.nature.com/articles/nmeth.2918 * Then assemble them + https://en.wikipedia.org/wiki/Gibson_assembly + 20-40 bp overlap + 5-15 oligos can be combined at once (~2 kb produced) * New technologies + https://static1.squarespace.com/static/ 5c981af7ebfc7fc8528d6564/t/5f4048cda662a571341b9a60/ 1598048462430/Alix+-+MDD+DNA+Writing.pdf About Reverse engineering SARS-CoV-2 Topics covid-19 Resources Readme Releases No releases published Packages 0 No packages published Contributors 8 * @geohot * @ajaykarpur * @ScottBrenner * @ronaldveis * @emilwidlund * @miugel * @wjjmjh * @hexpwn Languages * Python 100.0% * (c) 2021 GitHub, Inc. * Terms * Privacy * Security * Status * Docs * Contact GitHub * Pricing * API * Training * Blog * About You can't perform that action at this time. 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