To gain insight into how researchers of aging perceive the process they study, we conducted a survey among experts in the field. While highlighting some common features of aging, the survey exposed broad disagreement on the foundational issues. What is aging? What causes it? When does it begin? What constitutes rejuvenation? Not only was there no consensus on these and other core questions, but none of the questions received a majority opinion—even regarding the need for consensus itself. Despite many researchers believing they understand aging, their understanding diverges considerably. Importantly, as different processes are labeled as “aging” by researchers, different experimental approaches are prioritized. The survey shed light on the need to better define which aging processes this field should target and what its goals are. It also allowed us to categorize contemporary views on aging and rejuvenation, revealing critical, yet largely unanswered, questions that appear disconnected from the current research focus. Finally, we discuss ways to address the disagreement, which we hope will ultimately aid progress in the field.

RaTG13, MP789, and RmYN02 are the strains closest to SARS‐CoV‐2, and their existence came to light only after the start of the pandemic. Their genomes have been used to support a natural origin of SARS‐CoV‐2 but after a close examination all of them exhibit several issues. We specifically address the presence in RmYN02 and closely related RacCSxxx strains of a claimed natural PAA/PVA amino acid insertion at the S1/S2 junction of their spike protein at the same position where the PRRA insertion in SARS‐CoV‐2 has created a polybasic furin cleavage site. We show that RmYN02/RacCSxxx instead of the claimed insertion carry a 6‐nucleotide deletion in the region and that the 12‐nucleotide insertion in SARS‐CoV‐2 remains unique among Sarbecoviruses. Also, our analysis of RaTG13 and RmYN02's metagenomic datasets found unexpected reads which could indicate possible contamination. Because of their importance to inferring SARS‐CoV‐2′s origin, we call for a careful reevaluation of RaTG13, MP789 and RmYN02 sequencing records and assembly methods.

Pekar et al. (2022) propose that SARS-CoV-2 was a zoonotic spillover that first infected humans in the Huanan Seafood Market in Wuhan, China. They propose that there were two separate spillovers of the closely related lineages A and lineage B in a short period of time. The two lineages are differentiated by two SNVs; hence, a single-SNV A-B intermediate must have occurred in an unsampled animal host if the two-spillover hypothesis is correct. Consequently, confirmation of the existence of an intermediate A-B genome from humans would falsify their hypothesis of two spillovers. Pekar et al. identified and excluded 20 A-B intermediate genomes from their analysis. A variety of exclusion criteria were applied, including low read depth and the assertion of repeated erroneous base calls at lineage-defining positions 8782 and 28144. However, data from GISAID show that most of the genomes were sequenced to high average sequencing depth, appearing inconsistent with these criteria. The decision to exclude the majority of genomes was based on personal communications, with raw data unavailable for inspection. Multiple errors, biases, and inconsistencies were observed in the exclusion process. For example, 12 intermediate genomes from one study were excluded; however, 54 other genomes from the same study were included, indicating selection bias. Puzzlingly, two intermediate genomes from Beijing were discarded despite an average sequencing depth of 2175X; however, four genomes from the same sequencing study were included in the analysis. Lastly, we discuss 14 additional possible intermediate genomes not discussed by Pekar et al. and note that genome sequence filtration is inappropriate when considering the presence or absence of a specific SNV pair in an outbreak. Consequently, we find that the exclusion of many of the intermediate genomes is unfounded, leaving the conclusion of two natural zoonoses unsupported.

Understanding how SARS-CoV-2 entered the human population, thereby causing the COVID-19 pandemic, is one of the most urgent questions in science today. Two hypotheses are widely acknowledged as being most likely to explain the pandemic’s origin in late 2019: (i) the “natural origin” hypothesis that one or more cross-species transmissions from animals into humans occurred, most likely at the Huanan Seafood Market in Wuhan, China; (ii) the “laboratory origin” hypothesis, that scientific research activities led to the unintentional leak of SARS-CoV-2 from a laboratory into the general population. A recent analysis of SARS-CoV-2 genomes by Pekar et al. [ Science 377 :960-966 (2022)] claims to establish at least two separate spillover events from animals into humans, thus claiming to provide strong evidence for the natural origin hypothesis. However, here we use outbreak simulations to show that the findings of Pekar et al. are heavily impacted by two methodological artifacts: the dubious exclusion of informative SARS-CoV-2 genomes, and their reliance on unrealistic phylodynamic models of SARS-CoV-2. Absent models that incorporate these effects, one cannot conclude multiple SARS-CoV-2 spillovers into humans. Our results cast doubt on a primary point of evidence in favor of the natural origin hypothesis. Lay Summary: It is not known if SARS-CoV-2 spilled over from animals into humans at the Huanan Seafood Market, or arose as a result of research activities studying bat coronaviruses. Two recent papers had claimed to answer this question, but here we show those papers are both inconclusive as they fail to account for biases in how medical managers became alerted to SARS-CoV-2 and how public health authorities sampled early cases. Additionally, key data points conflicting with the authors’ conclusions were improperly excluded from the analysis. The papers’ methods do not justify their conclusions, and the origin of SARS-CoV-2 remains an urgent, open question for science.

Tyshkovskiy and Panchin have recently published a commentary on our paper in which they outline several “points of disagreement with the Segreto/Deigin hypothesis.” As our paper is titled “The genetic structure of SARS‐CoV‐2 does not rule out a laboratory origin,” points of disagreement should provide evidence that rules out a laboratory origin. However, Tyshkovskiy and Panchin provide no such evidence and instead attempt to criticize our arguments that highlight aspects of SARS‐CoV‐2 that could be consistent with the lab leak hypothesis. Strikingly, Tyshkovskiy and Panchin's main point of criticism is based on a false premise that we have claimed RaTG13 to be a direct progenitor of SARS‐CoV‐2, and their other points of criticism are either not valid, based on flawed mathematical analysis, or are unrelated to our hypotheses. Thus, the genetic structure of SARS‐CoV‐2 remains consistent with both natural or laboratory origin, which means that both the zoonotic and the lab leak hypothesis need to be investigated equally thoroughly.

Pangolins are the only animals other than bats proposed to have been infected with SARS-CoV-2 related coronaviruses (SARS2r-CoVs) prior to the COVID-19 pandemic. Here, we examine the novel SARS2r-CoV we previously identified in game animal metatranscriptomic datasets sequenced by the Nanjing Agricultural University in 2022, and find that sections of the partial genome phylogenetically group with Guangxi pangolin CoVs (GX PCoVs), while the full RdRp sequence groups with bat-SL-CoVZC45. While the novel SARS2r-CoV is found in 6 pangolin datasets, it is also found in 10 additional NGS datasets from 5 separate mammalian species and is likely related to contamination by a laboratory researched virus. Absence of bat mitochondrial sequences from the datasets, the fragmentary nature of the virus sequence and the presence of a partial sequence of a cloning vector attached to a SARS2r-CoV read suggests that it has been cloned. We find that NGS datasets containing the novel SARS2r-CoV are contaminated with significant Homo sapiens genetic material, and numerous viruses not associated with the host animals sampled. We further identify the dominant human haplogroup of the contaminating H. sapiens genetic material to be F1c1a1, which is of East Asian provenance. The association of this novel SARS2r-CoV with both bat CoV and the GX PCoV clades is an important step towards identifying the origin of the GX PCoVs.