Daniel S Helman, PhD

Mass photometry uses light to weigh individual molecules. I think it’s really compelling and useful. If you wanted to weigh a protein, for example, you shine light at it, and electrons in the protein respond by scattering some of that light. The amplitude of the scattered light wave is approximately proportional to molecular mass, meaning that larger proteins produce a "stronger" signal than smaller proteins. Special microscopes can detect these tiny, tiny signals by combining light scattered by a protein with light reflected from the glass slide beneath it. The two light waves interfere, producing a small change in brightness. Researchers calibrate those measurements using proteins with known masses. Now, usually, mass photometry weighs a molecule as it falls on top of glass. But for this paper, they describe a method to keep weighing the same molecule and watch its mass change as other molecules attach and detach, in real-time. Basically, they attached individual proteins to small patches of a lipid membrane, so each protein could move a little bit, but couldn’t drift out of view. They then measured the mass of that protein 497 times PER SECOND over the span of an entire hour. Every time the protein binds to anything (like an antibody, or its receptor, or a small molecule), the binding event shows up as a little spike in the data. So with the SARS-CoV-2 spike protein, for example, they could follow its mass rising and falling as the ACE2 receptor attached and detached. They measured how long the two stayed bound together, also: 64 seconds on average. They also watched antibodies attach one after another, producing up to three distinct increases in mass, matching the spike’s three binding sites. Really beautiful biophysics.

Great little review. The lipid membrane is probably the most underrated and poorly studied part of the cell. When people make "synthetic" cells, they usually do so using a single type of lipid. And yet, for reasons we don't yet understand, cells have dozens of different lipids in their membranes, some of which have remarkable properties. "It was recently shown," Sáenz writes, "that in deep-sea ctenophores, plasmalogens, a type of curvature-promoting lipid, keep membranes functional under extreme pressure." Oddly enough, when the J. Craig Venter Institute cut down a Mycoplasma cell's genome size to its near-minimum, and then studied the resulting organism, they "found around 90 different lipids, a number comparable to that of the naturally occurring mycoplasma from which its synthetic genome was derived. A minimal genome, it turns out, does not produce a minimal lipidome." Cells seem to *want* to have a high variance of lipids in their membranes, for reasons that are not clear. Furthermore, when the researchers found ways to finally cut down the number of lipids in the Mycoplasma membrane, the cells still found clever ways to get around their constraints. "The cell...resists lipidome minimization," in other words. In one case, the researchers gave the cells "a conventional phospholipid" in their growth medium, and the cells quickly "scavenge[d] the acyl chains through the activity of lipases and rebuil[t] a diverse lipidome from the pieces." They finally cut down the number of lipids in these cells to just two, but this caused the cells to grow slowly and become artificially enlarged. So one argument for why cells try to maintain such a panoply of lipids in their membranes might be because it "allows them to control otherwise coupled properties independently of one another." From the review: "Chain length, unsaturation, head-group chemistry and molecular shape provide chemical degrees of freedom for tuning membrane properties. Because changing any one feature (for example, a double bond or a longer or shorter chain) generally shifts several properties at once, a minimal or fixed composition offers only coupled control. But not all lipidomic degrees of freedom are equivalent. Some properties can be produced through many lipidomic solutions, whereas others require a specific molecular structure." Interesting throughout.