The method is based on cool ideas. In effect, it blurs the distinction between structure prediction and structure determination. That probably also means one should carefully rethink validation, i.e. how would one detect erroneous solutions? Exciting times! 😀

In general, when optimising a difficult target we have a choice to use prior information to restrain the set of solutions, or to keep some of it aside for validation. This approach is a very interesting exercise in how far one can go with using the available prior information in AlphaFold.

One problem with this approach is that our main tool to detect issues, the quality of the map, is gone. That is especially important for weak SNR data sets, where Einstein will be happy to emerge from noise.

The study with the organoids was spearheaded by Mehtap Bacioglu in Maria Grazie Spillantini's group. The work on primary cultures was led by Melissa Huang, who was previously in Will McEwan's group and who is now with us, in Michel Goedert's group.

When using limited amounts of seeds, we could see density for the methionine at position 337, confirming that we had indeed solved the structure of the seeded aggregates. However, we could also solve the structure of the seeds when using more seeds. This is an important warning for future studies.

In murine primary cortical cultures, we need overexpression of full-length human tau to get sufficient tau aggregation within the life-span of the cells. But then we also see robust seeded aggregation.

One practical step could be to limit CVs to a maximum of N papers, where the importance of each paper gets explained. N could vary for different purposes.

A cultural change in how we measure/perceive scientific productivity, away from numbers of papers, towards more meaningful measures, would be helpful for many aspects of science and how we organise it.

I agree. Oligomers have been a distraction for too long.

Over the last week I have had separate discussions with three people being disillusioned by how bad their colleagues are at their job. Large organizations seem worse. I wonder whether having line managers work together with their people, instead of just leading from above, is a good solution.

this is fantastic and I learned something new