A cool implication of the secondary nucleation story is that it could reconcile the “fibrils vs. oligomers” debate (which is toxic?) Fibrils can aid oligomer formation, and fibrils can be very different (depending on growth conditions) in their ability to nucleate new oligomers/fibrils.
The numbers work out too. Using solubility to calculate the fibril stability, the measured defect rate predicts a defect penalty that is very close to what is expected for an overhanging beta-strand.
In the context of a mature fibril, these overhangs will expose a beta strand with unsatisfied H-bonding groups. This is precisely what is needed to surmount the nucleation barrier predicted by our theory. www.sciencedirect.com/science/arti...
Homopolymers (like HTT) have mostly small alignment defects. But molecules like A-beta, with two separate aggregation hotspots, are prone to large overhangs. pubs.acs.org/doi/full/10....
Today’s paper shows that secondary nucleation occurs at defects sites and the number of defects can be controlled by growth conditions. Our microscopic theories explain the nature of these defects, how often they occur, and how they facilitate nucleation.
doi.org/10.1016/j.bp...
Meanwhile, our work showed that: 1) elongation is a search over beta-sheet alignments, and 2) that nucleation is limited by a conformational entropy barrier. A prediction of #1 is that fibrils will have alignment defects.
A key finding of the Knowles theory (@georg-meisl.bsky.social and others) is that the main factor driving amplification of aggregates is secondary nucleation (i.e., the fibril surfaces catalyze the formation of new fibrils). However, the mechanism of this has been unknown.
This paper brings together two (previously) disconnected amyloid theories:
1) Knowles group (Cambridge) theories relating mesoscale processes (elongation, nucleation, fragmentation) to macroscopic rates
2) Our group’s theories connecting microscopic degrees of freedom to the mesoscale rates.
Thrilled to contribute to this fantastic collaboration with @georg-meisl.bsky.social, @arosiolabeth.bsky.social, @tscheidt.bsky.social (many others). Lots of great experimental work went into this paper, but here's a brief thread on what I find exciting from the theory side.
doi.org/10.1038/s414...
Structural defects in amyloid-β fibrils drive secondary nucleation www.nature.com/articles/s41...
Congratulations, Ivar!
There is a tradeoff between mobility and affinity. Increasing length reduces binding cooperativity (for fixed valence) which initially aids mobility until entanglement kicks in.
I agree with your speculation of a publication bias. When developing our paper, I spoke to several groups sitting on unpublished negative results. We even changed the pitch of our paper to emphasize the (limited) regimes of acceleration, when the real message is about retardation.
Put simply: high concentrations facilitate reactions because you get more molecular collisions. However, molecules don't move well (or collide) when they are stuck together:
journals.aps.org/pre/abstract...
Multidisciplinary training, over time, produces the highest impact people
www.science.org/doi/10.1126/...
Physicist Leo Szilard, in a short science fiction story from 1948, describing how to retard science by making the funding application longer and harder than the proposed research - now called the ‘Szilard point’
Excited to share the first paper from my group with Gianluca Teza (MPI-PKS) and Attilio L. Stella (U Padova)! “Coarse-Graining via Lumping: Exact Calculations and Fundamental Limitations” shows when lumping is exact and when it fails even without approximations. arxiv.org/pdf/2512.11974
Not sure I have advice to give, but I will offer congratulations on the life/career achievement!
I don't know if I'm more relieved to hear that my cultural references aren't as old as I feared, or more concerned that the same bad idea emerged from independent sources.
It seems your coach was unable to tell the difference between a cartoon and an instructional video on coaching pedagogy
This was a running joke in a South Park episode. But, if there is one thing we have learned since it aired, there is a significant part of the population that is incapable of telling the difference between satire and reality.
Finally!
Very cool work. I also thought about Hwa's growth laws while reading the thread. Quantitative curves are great to stimulate chin scratching!
Here’s the thing, emerging scientists aren’t going to flee to do science elsewhere…they just won’t do the science.
We will lose at least one, if not two generations of knowledge if we don’t get this shit sorted out immediately.
The US is funding fewer grants compared to the past. The money is given in one lump sum instead a yearly infusion from a multi-year funded grant. This leads to more competition, less $ and time to do research. Not a win-win situation.
🧪🎁🔗 www.nytimes.com/interactive/...
"I, at any rate, am convinced that He is not playing at dice."
Einstein sent a letter to Max Born #OTD in 1926, in which he gave his oft-quoted objection to the probabilistic interpretation of the wavefunction in quantum mechanics. 🧪 ⚛️
You may be surprised by where this is headed. (1/n)
Talk titles for IDPSeminars on Dec 4th at noon central time. Alex Holehouse (Washington University in St. Louis): Sequence-to-ensemble with STARLING Birthe Kragelund (University of Copenhagen): Disordered protein complexes and the origins of life
We're back for our final seminar of 2025 with talks from @alexholehouse.bsky.social and Birthe Kragelund! 1 pm EST or 7 pm European time. If you're not already signed up, head on over to idpseminars.com to register!
A lot of complexity comes from thinking in terms of two-phase dilute/dense equilibrium. A three-state monomer/oligomer/dense framework is much easier. The monomer/oligomer and monomer/dense equilibria are easy to understand (and calculate) and the oligomer/dense comes along for free. 7/7
We show how to subtract oligomer effects from experimental data in order to reveal the solubility product phase boundary. The deviations from power law can then be used to understand the dense phase energy landscape. 6/7
Second, unlike salts, biomolecular condensates do not have strict stoichiometries. Variable stoichiometry in the dense phase bends the power law phase boundary, resulting in a larger two-phase region. 5/7
