It's a guided, but automated process. EMAN2 (the software used/partially written by the author), for instance, has a convolutional neural network particle picke

It's a guided, but automated process. EMAN2 (the software used/partially written by the author), for instance, has a convolutional neural network particle picker. So you can pick a few particles by hand, pick some noise, pick some bad particles, train a neural network, and then inference that network to pick the remaining particles throughout the tomogram. There are a variety of other methods too. There is simple 6 dimensional real-space cross correlation. You can place points by hand, or according to a model. For instance, if you are trying to identify viral spike proteins, and the virus is spherical, and the spike proteins are always on the surface of the sphere, you have a great starting point. So you can say "place points at n interval along the surface of this sphere" and then oversample the spherical surface. You then take a reference volume (can be generated a number of ways), and check each point you placed to see how well it matches the reference volume. You can allow for rotations and translations of the reference volume at each point, and if you find points that are too close together, you can merge them automatically. If you have a high contrast, relatively static protein (such as a ribosome), you can do 2D template matching in the tomogram, where you use a central slice (or maybe a collapsed projection) to do cross correlation in 3 dimensions instead of six (X translation, Y, translation, Z rotation). Or you can beef that up with more neural network/YOLO type stuff. EDIT: To expand on this, continuous density like membranes can be roughly modeled just with techniques like thresholding, watershedding, etc. There are some neural nets such as Membrain [0] and tomoseg [1] (also by the author of this paper), but membranes certainly are trickier. I typically segment membranes by hand (and do so rarely). [0] https://www.sciencedirect.com/science/article/pii/S0169260722003728 https://www.sciencedirect.com/science/article/pii/S016926072... [1] https://blake.bcm.edu/emanwiki/EMAN2/Programs/tomoseg https://blake.bcm.edu/emanwiki/EMAN2/Programs/tomoseg