Ebola infects neurons and keeps shedding virus for 120 days; a fish cancer spreads between fish
Brain organoids show that Ebola can infect neurons and keep releasing infectious virus for 120 days; melanomas in a brown bullhead population descend from a single clonal ancestor and spread from fish to fish. The boundaries of viral persistence and of transmissible cancer get rewritten at the same time.
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The argument · tap a timestamp to hear it
Three-tier scoring gives political appointees more room to pick projects
NIH has proposed replacing the numerical scores in grant review with three tiers — good, medium, poor — on the grounds that the current numbers are severely compressed, with large numbers of grants bunched at nearly the same score and very little discrimination between them; the three-tier system is already in use at NSF. Rich does not object to tiering as such, but he says the real problem is that all three of them now distrust NIH's leadership: vague tiers make it easier for political appointees to select projects on ideological grounds. He also recalls that NSF gave him partial funding back when his first grant was rejected.
— Rich ConditDetecting RNA is not persistence; what counts is whether virus is released
A team at the Bernhard Nocht Institute in Hamburg used human brain organoids to study Ebola's long-term persistence, and drew a distinction between two kinds of persistence: productive persistence, the continued release of infectious particles, and nonproductive persistence, where only RNA can be detected. microglia at MOI 1 or 10 remained persistently infected through 13 passages over 91 days; across the organoid as a whole the infection rate exceeded 90%, with virus produced continuously for 120 days. Once the definition is made explicit, ‘persistent infection’ can no longer be waved through on an RT-PCR positive alone — you have to show that complete virus is being released.
— Alan DoveEbola infects neurons directly, which had never been reported before
The team watched infection spread through the organoid: the virus advanced from the periphery toward the center, infecting neurons, astrocytes and microglia. Neuronal infection had never been reported before, which rewrites the earlier view that Ebola is not neurotropic. microglia clustered around the infected cells, suggesting that innate immunity was attempting a response; Lassa virus, used as a control, disappeared from the organoids within 48 days, while Ebola was still there. The difference suggests that replication in the brain is not incidental contamination.
— Alan DoveThe immune response both attacks and brakes, which helps the virus linger
What happens in an infected organoid is not simply destructive inflammation. The researchers detected pro-inflammatory cytokines, chemokines and anti-inflammatory mediators simultaneously in the infected brain organoids. This says that the host's inflammatory response is a self-balancing system, with an attack and a brake. For a persisting virus, a moderately suppressed immune environment is more favorable to long-term coexistence than a one-sided inflammatory storm.
The mutations found in organoids have never been seen in survivors
The authors acknowledge that the model is isolated from the in vivo environment and lacks contributors to immune-privileged status such as the blood-brain barrier; more importantly, the single-nucleotide variants that arise in the organoids have never been reported in survivors of Ebola virus disease, which points to a fundamental difference between the two. Many of the mutations are thought to reduce or block viral replication, and low-level replication may in fact be what allows the virus to maintain itself within the cell population. Persistence need not rest on high titer; it may rest on replication low enough not to trigger clearance.
Pollution is not the culprit: this cancer spreads between fish
Since 2012, fishermen on Lake Memphremagog (between Maine and Quebec) have repeatedly caught brown bullhead (Amiurus nebulosus) bearing raised black lesions, identified histologically as malignant melanoma. In sampling between 2014 and 2017, 23%–37% of the fish carried lesions. Suspicion initially fell on runoff pollution from Tropical Storm Irene in 2011 as the trigger, but the later data pointed in a rarer direction — the tumor itself can spread from fish to fish. The lake has become a natural site for observing how a cancer becomes a pathogen.
The lake's tumors all descend from one clone, and it came from elsewhere
Two genomic analyses corroborate each other. On the mitochondrial genome tree, all the tumor samples form a single monophyletic group, meaning they descend from a single ancestor; and the tumor sequences resemble neither the normal tissue of the same fish nor the normal tissue of other fish in the lake, whose sequences scatter across the tree. Single-nucleotide variant analysis of the nuclear genome likewise yields a monophyletic group, and these tumor genomes are closer to unaffected reference fish from New Hampshire and Maine than to the other fish in the lake — so the clone driving the transmission did not originate in this lake, but was introduced from somewhere else.
Human cancer mutations are each distinct; over half of these fish mutations are shared
The harder evidence comes from variant-sharing statistics. Across 16 tumor–normal tissue pairs, 245,000 tumor-specific SNVs and 61,000 brain-specific SNVs were identified; 59% of the tumor-specific SNVs are shared by at least 14 fish, whereas 83% of the brain-tissue-specific SNVs occur in only one fish. For comparison, in human melanoma databases 94% of SNVs are unique to a single cancer, and only 0.008% are shared by more than 10 cancers. Such a high proportion of shared variants in the fish tumors, the paper's authors argue, further supports the conclusion that these cancers come from the same clone and are transmissible.
In their own words · checked verbatim
I think the worst part, the tragic part about all this is that three of us are sitting here saying we don't trust the people at NIH. Yes. That's a tragedy.
Rich Condit16:26
So they draw this distinction here between two kinds of persistence, productive persistence, which is, yeah, there's infectious particles, and nonproductive persistence, which is RNA only.
Vincent Racaniello25:43
The barrier is immune recognition. You know, we have really good MHC systems who are outbred. And so any transplanted cells get rejected.
the rarity of transmissible cancers suggests evolutionary selection against them. But she said maybe we're not looking hard enough.
I don't know why you needed to make these pencil things. I guess because you could, right?
Vincent Racaniello1:35:29
It's not just capitalist. It's too capitalist. We've taken things a little too far these days.
Rich Condit1:37:36
Figures
| NIH's proposed number of review tiers | 3 | 8:13 |
| Days microglia remained persistently infected | 91 days | 31:49 |
| Share of the brain organoid infected | over 90% | 38:56 |
| Days the brain organoids kept producing virus | 120 days | 38:56 |
| Lesion rate in Lake Memphremagog bullhead | 23%–37% | 52:18 |
| Total tumor-specific SNVs identified | 245,000 | 1:03:54 |
| Share of human melanoma SNVs unique to a single cancer | 94% | 1:04:54 |
| Share of human melanoma SNVs shared by more than 10 cancers | 0.008% | 1:04:54 |
| Pencil tower apartment price | $15 million per unit | 1:35:29 |
| Estimated cost of demolishing the leaning pencil tower | $150 million | 1:35:29 |
Glossary
- productive persistence
- Continued release of infectious virus particles, rather than merely residual nucleic acid.
- nonproductive persistence
- A state in which viral RNA is detectable but infectious particles are no longer released.
- BSL-4
- The highest level of containment facility, used for handling the most dangerous pathogens.
- MOI
- The ratio of virus particles added to the number of cells when infecting them.
How to listen
Virologists and researchers working on neurological infection, cancer biologists studying transmissible tumors, and research administrators who care about the NIH funding ecosystem and biosafety policy.
The last half hour on the pencil tower and the woodworking book recommendation has nothing to do with the main pathogen story, and can be skipped.