This episode of This Week in Evolution (TWiEVo 117) features Vincent Racaniello and Nels Elde discussing the unsettling impact of political interference on scientific research, prompted by Elde's NIH R35 grant renewal being flagged for "dangerous gain-of-function" research.
The discussion delves into a scientific paper by Elde's lab, "Hidden evolutionary constraints dictate the retention of coronavirus accessory genes," which examines the mouse hepatitis virus (MHV) and its ORF2 gene, as well as parallels with SARS-CoV-2's ORF8. The research reveals that certain "non-coding features," likely secondary RNA structures, impose hidden evolutionary constraints, leading to the unexpected retention of genes even when their protein-coding function is mutated or lost, a finding that challenges the "less is more" evolutionary paradigm. This experimental evolution work, performed under strict biosafety conditions with a non-human virus, provides fundamental insights into coronavirus biology and diversification.
The hosts critically analyze the NIH's decision, presenting it as politically motivated, scientifically incoherent, and detrimental to public health and the American scientific enterprise. They highlight the chilling effect on researchers, the misrepresentation of evidence (e.g., in the context of mRNA vaccines), and the potential for a dangerous shift towards state-level funding, all of which threaten the future of basic science and pandemic preparedness. The episode concludes by emphasizing the crucial role of science communication, mentorship, and community support in navigating these challenging times.
Exploring Political Interference and Coronavirus Evolution
0:00 Introduction to TWiEVo 117: Hosts Vincent Racaniello and Nels Elde (from MicrobeTV and Elde Lab Studios in Salt Lake City) introduce the episode, emphasizing its unusual focus due to current events. They thank moderators and welcome international listeners.
0:13 Political Interference in Science: Elde shares his experience of receiving a "jarring letter" from the National Institutes of Health (NIH) suspending his R35 grant renewal, flagging his virus evolution research as "dangerous gain of function."
0:41 NIH's "Dangerous" Definition: The letter stated that research on biological agents "has the potential to significantly endanger lives of American citizens if left unrestricted" and could cause "widespread mortality."
0:50 Critique of NIH's Stance: Racaniello vehemently labels the NIH's reasoning as "freaking lies" and a "political agenda," arguing it lacks scientific understanding and focuses on keywords (e.g., human gene into a virus) rather than actual risk.
1:09 Impact on Elde's Grant: NIH funds cannot be used for the flagged research, which Elde confirms is no longer funded by NIH. He frames this as part of a larger "category 4 hurricane" for scientific enterprise.
1:21 Importance of Science Communication: Elde stresses the need for open channels to discuss scientific research and its importance, especially against "headwinds" and "turbulence."
1:45 World Mosquito Day: A brief, lighthearted interlude noting mosquitoes as the most dangerous animal in terms of human mortality.
1:50 Acknowledging Support for Science Communication: Hosts thank supporters, underscoring its necessity in an environment where science is "controlled by politics."
1:52 Discussion of Presidential Order: Racaniello mentions a presidential order for political review of NIH grants, fearing that it will filter out "leftist stuff like virology."
2:27 Historical Context of Coronavirus Research on TWiEVo: Elde notes his lab's relatively new focus on coronaviruses, and reflects on TWiEVo's extensive coverage of SARS-CoV-2 since February 2020, highlighting the podcast as a historical record.
2:40 Less Is More Evolution: The general principle that viruses, especially RNA viruses, tend to lose unneeded genetic material to maintain fitness (e.g., polio virus quickly "spitting out" GFP).
2:50 Research Paper: "Hidden evolutionary constraints dictate the retention of coronavirus accessory genes"
2:50 Main Goal: To understand how viruses acquire and retain host genes, and how these genes diverge to benefit the virus.
2:50 Unexpected Finding: A "control experiment" showed that a mutated, non-functional accessory gene (NS-2 in ORF2) in mouse hepatitis virus (MHV) was retained despite expectations of its loss, violating the "less is more" rule.
3:18 Hypothesis for Retention: This retention suggests "non-coding features" or secondary RNA structures within the gene sequence are crucial for virus viability, indicating a new layer of gene regulation.
Used MHV (a mouse virus, BSL-2 conditions, never infected humans).
Created a "weakened virus" with a mutation removing phosphodiesterase (PTE) function in the NS-2 gene (ORF2).
Inserted a human phosphodiesterase gene (AAPP7) into ORF4 as a compensatory mechanism.
Serially passaged the virus in two cell lines: mouse macrophages (where OAS-RNase L pathway is strong, putting selective pressure on the virus) and L2 fibroblasts (where OAS-RNase L is weak, relaxing selective pressure).
In L2 cells (relaxed selection), the human AAP7 gene (in ORF4) was lost, as predicted by "less is more."
However, in both macrophages and L2 cells, the mutated viral NS-2 gene (ORF2) was retained, even after 15 passages.
This indicates a non-coding functional constraint on ORF2, likely secondary RNA structure, beyond its protein-coding role.
4:42 Peer Review and Further Insights: A reviewer's suggestion led to analyzing subgenomic RNA (sgRNA) abundance.
4:42 Coronavirus Replication & sgRNAs: Coronaviruses produce a "nested doll" of sgRNAs, with shorter ones (like spike protein mRNA) being more abundant.
4:57 Spike Protein Abundance: In L2 cells, passaged viruses showed a five-fold increase in sgRNA encoding spike protein. This suggests viruses optimize spike abundance for cell-to-cell infection when host immunity is relaxed.
5:10 Trade-offs and Safety: The experiments reveal viral "tricks" but also their trade-offs. More spike protein might aid infection in cell culture but would be a target for a full immune response in an animal. This highlights the safety and value of studying viruses in controlled experimental systems.
5:26 Application to SARS-CoV-2: The findings from MHV's ORF2 apply to SARS-CoV-2's ORF8.
5:26 ORF8 in SARS-CoV-2: ORF8 was known to be lost in early SARS-CoV-1 and has debilitating mutations (stop codons) in SARS-CoV-2 variants (B.1.1.7, XBB.1.x).
5:36 Computational Analysis: Despite these mutations, ORF8 sequences are largely retained across millions of SARS-CoV-2 sequences, similar to MHV's ORF2, supporting the "hidden constraint" hypothesis.
5:59 Engineering Challenges: The complexity of these hidden constraints (e.g., RNA folding, gene order dictating protein abundance) makes engineering viruses incredibly difficult, reinforcing the idea that claims of engineered viruses are uninformed.
6:10 The Danger of Political Decisions: The hosts strongly argue that the NIH's decision is driven by politics, based on a misunderstanding of gain-of-function research, and creates a "chilling effect" on vital scientific inquiry.
6:27 Re-framing the Danger: Elde re-frames the NIH's language: "Pathogens have the potential to endanger the lives of American citizens if left unstudied and unrestricted."
6:41 The Paradoxical Situation: The government simultaneously restricts research on dangerous viruses while threatening protections (like vaccines) against them.
7:10 Chilling Effect & Self-Censorship: Scientists (PIs) are intimidated, potentially leading to self-censorship, which experts like David Relman and Marc Lipsitch warn is more dangerous.
7:10 Damage to Public Health: Ending such studies is detrimental to health security and public health.
7:10 Erosion of Public Trust: Misrepresenting evidence for policy decisions erodes public trust.
7:10 Funding Cuts: Billions of dollars in federal funding have been clawed back, threatening basic science and future medical breakthroughs (e.g., mRNA vaccines for cancer).
7:10 Project 2025 & State Block Grants: Concern about a political agenda (Project 2025) potentially dissolving NIH into state-level funding, which would destroy American science by lacking necessary expertise for peer review.
7:10 Polarization & Immigration: The increasing political polarization and barriers to immigrant scientists further undermine the strength and global leadership of US science.
7:27 First Pick: The news piece in Science detailing NIH's suspension of pathogen studies over "gain-of-function" concerns.
7:34 Second Pick: A short essay by Brandon Gout, "On mentorship and acts of kindness," emphasizing the importance of community support, mentorship, and work-life balance (e.g., providing childcare at scientific meetings).
7:48 Vincent's Pick of the Week: An opinion piece by Jake Scott in Stat News, "Kennedy's case against mRNA vaccines collapses under his own evidence." Scott argues Kennedy's 181-page document, used to justify terminating mRNA vaccine funding, actually supports expanding such research and is intellectually dishonest.
7:57 Conclusion: The hosts thank listeners and moderators, emphasize the critical need for science communication and support, and encourage continued curiosity.