D20 The Binding Of Isaac
Garcia Miller
The story of the binding of Isaac (Genesis 22) has always troubled me, and reading it again this year has been no different. It's disturbing, even angering, to see commentators talk about Abraham suspending his compassion for his son in order to pursue his perceived will of The Eternal, as if that were a meritorious action. In my opinion, it is not.
Pardon me for a moment of pop culture, but it reminds me of a scene from Batman Begins in which Bruce Wayne is asked to execute a man as part of his initiation into The League of Shadows. He shows a compassion that makes him hesitate to do what is asked of him. When told by his mentor that his compassion is a quality his enemies will not share, Bruce replies, "That's why it's so important. It separates us from them."
Compassion is an important quality, and yet Abraham seems all too willing to forgo that quality. He doesn't even argue with The Eternal, as he did when he learned that Sodom was to be destroyed. Instead, he quietly and willingly sets about to comply with the command.
A God who asks us what the text appears to ask is not the true God but one whom we fashion in our own image. We often believe that God wants us to sacrifice our children to an imagined demand. But then it is not God who is cruel, but we; it is we who all too frequently are prepared to immolate our offspring to satisfy our own concept of duty and who will restrain our compassion before our own sense of righteousness. The history of humanity is replete with misdeeds committed in the name of religion.
What is the overarching theme of Abraham's story? He's a rebel. He's a monotheist in a world of polytheists. He fights a battle and returns the spoils of war to Sodom, a city known for being inhospitable, when he would have had every right to keep them. He argues with The Eternal to ensure that righteous people are not destroyed when judgement falls on Sodom. All this doesn't jibe with him killing his own son just because The Eternal told him to.
What if the story, instead, is a metaphor? What if, instead of being about obedience to The Eternal, it is really about the dangers of religious fanaticism? What if, instead of The Eternal testing Abraham, Abraham is testing The Eternal?
There are a couple of ways to look at it. One way is to take The Eternal stopping Abraham not as an external vision as portrayed in the text, but rather an internal triumph of human compassion over a fanatical zeal that could lead a person to do violence in the name of God. This, in and of itself, would be a rebellious notion in an age when human sacrifice was not unheard of.
But perhaps even more rebellious is the idea that Abraham was testing The Eternal, calling The Eternal's bluff. Abraham has already called The Eternal to the carpet once, challenging God as the Judge of all the earth to do justly. What's to keep Abraham from doing it in this instance as well?
This would explain the silence, as well as the language of the text where Abraham indicated to the servants that both he and Isaac would return, and later to Isaac when he said that God would provide the ram for the offering. For the Judge of all the earth to do justly, the Eternal could not let Abraham kill his own son. If Abraham knew this, he could have been seeing how far things would go, but with no intention to actually go through with the sacrifice. And if The Eternal had not stopped him, Abraham himself would have stopped it and probably would have had another little chat with God about doing the right thing.
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Chronic hepatitis C virus (HCV) infection occurs in about 3 percent of the world's population and is a major cause of liver disease. HCV infection is also associated with cryoglobulinemia, a B lymphocyte proliferative disorder. Virus tropism is controversial, and the mechanisms of cell entry remain unknown. The HCV envelope protein E2 binds human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Binding of E2 was mapped to the major extracellular loop of CD81. Recombinant molecules containing this loop bound HCV and antibodies that neutralize HCV infection in vivo inhibited virus binding to CD81 in vitro.
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A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world1,2,3. Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1,2,3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.
The emergence of the highly pathogenic coronavirus SARS-CoV-2 in Wuhan and its rapid international spread has posed a serious global public-health emergency1,2,3. Similar to individuals who were infected by pathogenic SARS-CoV in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, patients infected by SARS-CoV-2 showed a range of symptoms including dry cough, fever, headache, dyspnoea and pneumonia with an estimated mortality rate ranging from 3 to 5%6,7,8. Since the initial outbreak in December of 2019, SARS-CoV-2 has spread throughout China and to more than 80 other countries and areas worldwide. As of 5 March 2020, 80,565 cases in China have been confirmed with the infection and 3,015 infected patients have died ( -coronavirus-2019/situation-reports/). As a result, the epicentre Wuhan and the neighbouring cities have been under lockdown to minimize the continued spread and the WHO (World Health Organization) has announced a Public Health Emergency of International Concern owing to the rapid and global dissemination of SARS-CoV-2.
Coronaviruses use the homotrimeric spike glycoprotein (comprising a S1 subunit and S2 subunit in each spike monomer) on the envelope to bind to their cellular receptors. Such binding triggers a cascade of events that leads to the fusion between cell and viral membranes for cell entry. Previous cryo-electron microscopy studies of the SARS-CoV spike protein and its interaction with the cell receptor ACE2 have shown that receptor binding induces the dissociation of the S1 with ACE2, prompting the S2 to transit from a metastable pre-fusion to a more-stable post-fusion state that is essential for membrane fusion9,10,11,12. Therefore, binding to the ACE2 receptor is a critical initial step for SARS-CoV to enter into target cells. Recent studies also highlighted the important role of ACE2 in mediating entry of SARS-CoV-21,13,14,15. HeLa cells expressing ACE2 are susceptible to SARS-CoV-2 infection whereas those without ACE2 are not1. In vitro binding measurements also showed that the SARS-CoV-2 RBD binds to ACE2 with an affinity in the low nanomolar range, indicating that the RBD is a key functional component within the S1 subunit that is responsible for binding of SARS-CoV-2 by ACE213,16.
The cryo-electron microscopy structure of the SARS-CoV-2 spike trimer has recently been reported in two independent studies13,17. However, inspection of one available spike structure revealed the incomplete modelling of the RBD, particularly for the receptor-binding motif (RBM) that interacts directly with ACE217. Computer modelling of the interaction between the SARS-CoV-2 RBD and ACE2 has identified some residues that are potentially involved in the interaction; however, the actual residues that mediate the interaction remained unclear18. Furthermore, despite detectable cross-reactive SARS-CoV-2-neutralizing activity of serum or plasma from patients who recovered from SARS-CoV infections15, no isolated SARS-CoV monoclonal antibodies are able to neutralize SARS-CoV-216,17. These findings highlight some of the intrinsic sequence and structure differences between the SARS-CoV and SARS-CoV-2 RBDs.
The epitopes of SARS-CoV neutralizing antibodies m396 and 80R, which target the RBD, are labelled in the SARS-CoV sequence aligned with the sequence of SARS-CoV-2 RBD. Epitope residues of m396 are indicated by black dots; epitope residues of 80R are indicated by red dots.
The structure was determined using the molecular replacement method with PHASER in the CCP4 suite25. The search models used included the ACE2 extracellular domain and SARS-CoV RBD (PDB code 2AJF). Density map improvement by updating and refinement of the atoms was performed with ARP/wARP26. Subsequent model building and refinement were performed using COOT and PHENIX, respectively27,28. Final Ramachandran statistics: 96.44% favoured, 3.56% allowed and 0.00% outliers for the final structure. The structure refinement statistics are listed in Extended Data Table 1. All structure figures were generated with PyMol29.
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