Immune cells swell toward bursting while their unwound DNA is still inside the nucleus

The work began as two projects that did not look related. Manasi Sawant, a postdoctoral scholar and co-lead author, was following how chromatin loosens during NETosis through two of the proteins that keep DNA wound, H1 and HP1-alpha ^[8]. The share of each protein floating free in the nucleus, set against the share still bound to chromatin, gauges how far the DNA has unwound ^[8]. As NETosis went on, HP1-alpha left the chromatin as expected. Sawant could not find it floating in the nucleus ^[9].

Aidan Cabral, a bioengineering PhD student and the other co-lead author, was studying why the membrane gives way ^[14]. He found membrane tension rising before the chromatin had left the nucleus at all ^[5]. "This was really surprising, that changes in chromatin compaction in the nucleus can have a huge, long-range impact on the mechanics of the entire cell," Cabral said ^[7].

That timing is the cleanest part of the result. Strain that starts while the chromatin is still in the nucleus cannot come from escaped chromatin pressing on the membrane ^[5][6]. It also tied Cabral's tension readings to the proteins Sawant had lost track of ^[10].

In the published account, the link between shed proteins and swelling is a correlation, and osmosis is the team's proposal for how it works ^[10][11]. The nearest thing to a causal test is the team's report that it could prevent or speed up NETosis in cells ^[12]. The account does not say which immune cells were studied, whether they came from people or mice, how the team tipped the process each way, or whether any of it has been tried in animals.

NETosis, in which certain immune cells burst and release their DNA to trap pathogens, is critical for clearing infections and a liability in autoimmune diseases ^[1][2]. The article presents the newly identified levers as a route to new therapies for autoimmune diseases, cancer and more ^[15]. I think the target is plausible, because the strain begins before the nucleus releases its DNA, early in a sequence whose order had been poorly understood ^[3][5]. A drug that slowed bursting in autoimmune disease would still have to leave enough NETosis to clear infections ^[2].

Chromatin also loosens when healthy cells replicate and when cancer cells mutate and become drug-resistant, and Sawant hoped the NETosis work would teach her about those processes too ^[13]. Hawa Racine Thiam, the Stanford assistant professor of bioengineering who led the study published in Nature Communications, said that "if we understand those behaviors, we can start to engineer those behaviors" ^[4][16].