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Many viruses use a 2-step authentication process to enter cells, involving binding to a receptor and spike protein cleavage. Virologists have been adding furin cleavage sites to viruses since 1992, increasing their virulence. SARS-CoV-2, which likely originated from nature, contains unique furin cleavage site codons not typical in coronaviruses. This suggests a low probability of natural origin.

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In 1965, coronavirus was identified as a pathogen that could be modified for various purposes. The first human manipulation experiment took place in 1966, followed by transatlantic data sharing in 1967. In the 1970s, coronavirus was modified in animals like pigs and dogs. By 1990, it was discovered that coronavirus caused gastrointestinal issues in dogs and pigs, leading to Pfizer filing the first spike protein vaccine patent. The spike protein was not a new problem, as it was known since 1990. Vaccines for coronavirus have been ineffective due to its ability to mutate quickly, as stated in numerous independent scientific publications. In 2002, the University of North Carolina Chapel Hill patented an infectious replication defective clone of coronavirus, funded by Anthony Fauci. This suggests that SARS was engineered and not a naturally occurring phenomenon.

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We isolated coronaviruses from animals in the past to understand their threat to other species by culturing them on different cell types. This process, known as gain of function, involves enriching mutants that can infect new species. The speaker emphasizes that mass vaccination in humans is a significant gain of function experiment, leading to virus evolution. This real-world experiment involves constant virus changes due to human-to-human transmission under vaccine pressure.

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Dr. Kizzmekia Corbett and her team have been studying spike proteins in viruses for the past 10 years. They discovered that controlling the spike protein's shape is crucial for creating effective vaccines. Using their knowledge from previous research on MERS coronavirus, they quickly applied their techniques to develop a vaccine for the current virus in collaboration with Moderna. By January 10th last year, they obtained the virus sequences and produced the vaccine over the weekend. They tested the vaccine on mice and found that it generated antibodies. Dr. Corbett mentions that they are now working on addressing the variants of the virus.

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Research on potential pandemic pathogens, known as gain of function studies, has led to valuable public health insights. Previous NSABB reports support this. While I won't argue for the necessity of this research, there are many freely available studies showing how mutations identified through these studies have helped us prepare for epidemics and pandemics.

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Ralph Barrick from the University of North Carolina discusses synthetic genomics of SARS. He explains the structure and genome organization of the SARS coronavirus and its various proteins. Barrick then discusses the use of synthetic genomics as a platform to control emerging infectious diseases, particularly focusing on SARS. He explains the process of synthesizing a portfolio of spike glycoprotein genes to capture the heterogeneity of the virus. Barrick also discusses the use of synthetic deoptimization schemes to attenuate SARS pathogenesis and the rewiring of SARS coronavirus transcription circuits to further attenuate viral pathogenesis. He concludes by highlighting the potential of synthetic genomics and universal attenuation schemes for developing rapid response platforms and vaccines against emerging coronaviruses.

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The coronavirus spike protein's shape before interacting with our cells is key to triggering an antibody response. To study this, we create the spike protein in the lab, maintaining its precise shape. This is achieved using a "clamp"—a small fragment of HIV protein—that holds the spike protein in its natural, pre-interaction conformation. This ensures the lab-made protein accurately reflects the virus's structure, allowing for effective antibody response studies.

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Speaker 0: I read the sequence and it's high-resolution. Speaker 1: It may seem low at first, but it's understandable. Speaker 0: This is written in a loop. Speaker 1: This is the genetic sequence of the spike protein. The issue is that the model RNA has a sequence that surprised me. We need to design it a bit. It contains part of the sequence SB4T, which is necessary for gene expression. The problem is that it is found in a virus that has negative effects. Also, there is another problem with this sequence. The DNA that has been transferred so far becomes more susceptible to mutation. It's a problematic point. Speaker 1: So, this SB4T sequence is also included in the promoter of this SB method, which allows it to migrate to the nucleus. Speaker 0: This is quite famous. Speaker 1: Yes, it is. The issue is that it has no relation to the process of synthesizing the messenger RNA. Speaker 0: Why did they keep the promoter sequence in the SB4T that has nothing to do with the camera's perspective in the messenger RNA synthesis process?

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We created coronaviruses by assembling a synthetic bat genome with the SARS clone. The genome was split into 5 kilobyte pieces with unique restriction sites to allow directional assembly. Initially, the virus couldn't replicate due to an entry defect, so we replaced the receptor binding domain with one from the human epidemic strain. This modification resulted in a virus that replicated efficiently. The growth curve data supported this success.

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The spike protein on the surface of the coronavirus is crucial for its structure and interaction with our cells. To trigger a strong antibody response, Keith replicates the spike protein in the lab. He uses a small piece of HIV protein as a clamp to lock the spike protein into its original shape. This ensures that the spike protein maintains its structure and effectiveness.

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Chinese researchers have created a super virus by combining a protein from bats with the SARS virus found in mice. This virus could potentially infect humans, although it is currently only being studied in laboratories. The debate over the risks of this research is not new, with some scientists arguing that the benefits outweigh the potential dangers. However, others are concerned about the possibility of the virus directly infecting humans without an intermediate species. The US government had previously suspended funding for research aiming to make viruses more contagious, but this did not stop the Chinese research on SARS. Some experts believe the chances of the virus spreading to humans are minimal compared to the potential benefits, while others disagree.

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Ralph Barrick from the University of North Carolina discusses synthetic genomics of SARS in this video. He explains the structure and genome organization of the SARS coronavirus and its various proteins. Barrick also discusses the use of synthetic genomics as a platform to control emerging infectious diseases and develop vaccines. He presents the results of experiments involving the synthesis of different SARS virus strains and their ability to infect human airway cells. Barrick also discusses the use of deoptimized codons to attenuate SARS pathogenesis and the rewiring of SARS coronavirus transcription circuits to further attenuate viral pathogenesis. He concludes by highlighting the potential of synthetic genomics and universal attenuation schemes to rapidly produce candidate live virus vaccines for emerging pathogens.

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Scientists sequence the virus and compare it to known pathogens like SARS. They discovered similar coronaviruses in bats and focused on the spike protein that attaches to cells. Chinese researchers created pseudoparticles with spike proteins from these viruses to test their binding to human cells. Each step of this process helps determine if the virus can become pathogenic in humans. Manipulating the spike protein in the lab is crucial for understanding the zoonotic risk. By obtaining the sequence, scientists can predict the virus's behavior more accurately.

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In 2015, the National Library of Medicine published a study by 15 virologists and medical experts warning that SARS-like bat coronaviruses pose a potential threat to humans. The scientists, with decades of experience in studying coronaviruses, examined how SARS and MERS transmitted among humans. They modified a strain of coronavirus from Chinese horseshoe bats using gain of function technology and injected it into mice spinal cords. This study not only highlights the dangers of coronaviruses in bats but also demonstrates efforts to amplify the virus's contagion ability to better understand and prepare for future outbreaks.

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Ralph Barrick from the University of North Carolina discusses synthetic genomics of SARS in this video. He explains the structure of the SARS coronavirus particle and its important glycoprotein spikes. Barrick also discusses the synthetic resurrection and reconstruction of various zoonotic SARS viruses and their applications in therapeutics and vaccine design. He touches on codon deoptimization as a way to attenuate SARS pathogenesis and rewiring SARS coronavirus transcription circuits as a universal strategy to attenuate viral pathogenesis. Barrick concludes by discussing the potential of synthetic genomics and transcription circuit redesign as a platform to control emerging infectious diseases and develop rapid response platforms for future epidemics.

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The spike protein of the coronavirus plays a crucial role in triggering a strong antibody response. To study it in the lab, Keith uses a small fragment of HIV as a clamp to lock the spike protein into its original shape. This helps maintain the structure of the virus on its surface.

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Evolutionary virologists analyzed viral sequences from the current outbreak and in bats. They determined that the mutations required for the virus to jump from an animal to a human are entirely consistent with its evolutionary path. A paper detailing this research will be made available, although the authors are not currently named.

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The speaker discusses the Furin cleavage site found on the surface of the virus and its spike proteins. They explain that two enzymes, Furin and TMPRSS2, play a role in cutting the spike protein. The speaker mentions that the Spike protein is abundantly expressed in the respiratory tract, which is relevant to the virus's impact on the respiratory system. They also highlight the presence of a unique insert called PRRA in the virus, which is not found in similar viruses. The speaker questions the origin of this insert and mentions a patent from Moderna that includes a similar sequence. They find this odd and intriguing.

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In South America and Southeast Asia, there are many bat species carrying unknown viruses, making them potential sources of future pandemics. The USAID EPT predict program and NIAID funding allowed researchers to predict and prepare for emergencies like the SARS outbreak. They discovered that SARS-like viruses originate from bats in China, with some being almost identical to SARS. Surveillance of bat hunters and nearby residents revealed the potential for spillover into human populations. While there are no vaccines or antivirals for these diverse coronaviruses, scientists can manipulate them in the lab by studying their spike proteins. This knowledge can aid in the development of better vaccines and therapeutics. However, predicting and anticipating pandemics does not guarantee prevention.

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The speaker explains that the spike protein on the coronavirus is crucial for its structure and interaction with our cells. To trigger a protective antibody response, Keith replicates the spike protein in the lab and locks it into the same shape using a clamp-like protein. Surprisingly, this clamp-like protein is a small fragment of HIV.

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Researchers have discovered various coronaviruses in bats, including ones similar to SARS. They focused on the spike protein, which attaches to cells, and conducted experiments in China. By inserting spike proteins from these viruses into pseudoparticles, they tested their ability to bind to human cells. This process allowed them to understand the potential pathogenicity of the virus in humans.

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Scientists can learn how to teach the flu virus how to infect human tissue, and some are already doing this. The scientific community isn't trying to cause a pandemic, but they are arrogant about their ability to contain a respiratory pathogen. COVID evolved from scientific experiments in a laboratory that was trying to do good things, like make a vaccine vector, but it escaped, and over 20,000,000 people died. Nature will continue to try to change, but the species barrier for amino acids is pretty high. Some scientists believe gain of function research is needed to protect humanity against emerging pathogens, but they don't consider the fact that they may be emerging them like with COVID.

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We focus on viral families that have transmitted from animals to humans. When we find a virus that resembles a known dangerous pathogen, like SARS, we examine its spike protein, which attaches to cells. Chinese researchers create pseudo particles with these spike proteins to test if they bind to human cells. This process helps us identify viruses that could potentially be harmful to humans. By narrowing down the field and reducing costs, we end up with a small number of viruses that appear to be dangerous. We then investigate if people living in the same region as the animals carrying these viruses have developed antibodies.

Lex Fridman Podcast

Dmitry Korkin: Computational Biology of Coronavirus | Lex Fridman Podcast #90
Guests: Dmitry Korkin
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In this conversation, Lex Fridman interviews Dmitry Korkin, a professor specializing in bioinformatics and computational biology. Korkin's group recently reconstructed the 3D structure of COVID-19 proteins, creating a structural genomics map that is openly available to researchers. They discuss the biology of viruses, particularly COVID-19 and SARS, and how computational methods can aid in understanding viral structures to develop antiviral drugs and vaccines. Korkin describes viruses as "machines" that efficiently perform limited functions and adapt through evolution. He expresses concern about naturally occurring viruses, citing the emergence of new strains of influenza and coronaviruses as significant threats. The conversation touches on the differences between viruses like smallpox and coronaviruses, emphasizing the contagiousness of smallpox compared to COVID-19. They explore how viruses infect host cells, focusing on the spike protein's role in binding to human receptors. Korkin highlights the importance of understanding viral proteins to design effective vaccines and antiviral drugs. He mentions the potential for universal vaccines that could combat various strains of influenza. The discussion also covers the collaborative nature of scientific research during the pandemic, with rapid sharing of knowledge and preprints. Korkin emphasizes the need for continued research into viral mutations and the development of antiviral drugs, such as remdesivir, which targets viral replication. The conversation concludes with reflections on the fragility of human life in the face of viral threats and the hope that scientific advancements can provide solutions.

Lex Fridman Podcast

Dmitry Korkin: Evolution of Proteins, Viruses, Life, and AI | Lex Fridman Podcast #153
Guests: Dmitry Korkin
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In this episode, Lex Fridman converses with Dmitry Korkin, a professor specializing in bioinformatics and computational biology. Korkin discusses the complexity of proteins, emphasizing that while proteins are fundamental to life, their functional units, known as protein domains, are crucial for understanding their roles. He explains that proteins often consist of multiple domains that can perform various functions, and their evolutionary history reveals a modular complexity. The conversation shifts to the spike protein of SARS-CoV-2, highlighting its intricate structure and the challenges in studying it. Korkin notes that recent advancements in cryo-electron microscopy have allowed for better understanding of such proteins. He discusses the implications of understanding viral structures for vaccine development and treatment strategies, including designing nanoparticles that mimic viral proteins to block infection. Korkin also addresses the evolutionary dynamics of viruses, expressing concern over mutations that may arise as the virus spreads among different species. He reflects on the rapid scientific advancements made during the COVID-19 pandemic, particularly in sequencing and understanding the virus's evolution. The discussion touches on the broader implications of protein evolution, including the concept of alternative splicing and the interplay between genes and proteins. Korkin shares insights on the potential for machine learning to aid in protein design and the ethical considerations surrounding engineered viruses. Finally, Korkin expresses optimism about the future of scientific discovery, particularly with tools like AlphaFold, which has revolutionized protein structure prediction. He concludes with reflections on the importance of family and personal connections, sharing a poem that resonates with themes of longing and magic.
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