alexholehouse

For a nice primer on what biological phase separation is, see this (non-paywalled) general audience article from earlier this year in Nature (https://www.nature.com/articles/d41586-018-03070-2).

Some other work on phase separation as a means for primordial evolution and biochemistry includes a paper from Christine Keating in 2012 (WAY WAY ahead of the curve) [1], elegant work by Frank Jülicher [2], and more recently a nice paper from Keating and Phil Bevilacqua [3].

These papers (IMO) tie rather nicely into some theoretical predictions on self-organization from Jeremy England [4].

[1] Keating, C.D. (2012). Aqueous phase separation as a possible route to compartmentalization of biological molecules. Acc. Chem. Res. 45, 2114–2124.

[2] Zwicker, D., Seyboldt, R., Weber, C.A., Hyman, A.A., and Jülicher, F. (2016). Growth and division of active droplets provides a model for protocells. Nat. Phys. 13, 408.

[3] Poudyal, R.R., Pir Cakmak, F., Keating, C.D., and Bevilacqua, P.C. (2018). Physical Principles and Extant Biology Reveal Roles for RNA-Containing Membraneless Compartments in Origins of Life Chemistry. Biochemistry 57, 2509–2519.

[4] England, J.L. (2013). Statistical physics of self-replication. J. Chem. Phys. 139, 121923.

Seeing this happen in real cells in realtime would be – I would have thought – technically almost impossible. We're at the cusp of viewing the formation/loss of clusters of RNA POL or mediator clusters with the most advanced super-res (see Ibrahim Cissé's work) but these are comparatively massive protein clusters, so the idea of being able to view DNA structural transitions at [effectively] single-molecule resolution where that transition involves a few nucleotides in a non-perturbative way seems like a reach.

Seems like the obvious next step is to break 'em with synonymous mutations and ask if there's any detectable phenotype.

Edit: For clarity - all the in cell work is cultured cell lines and not cells taken from an animal model or in situ imaging.

Literally my only point was that 'this might not matter for biology because we've not even seen it in cells' is no longer true. It still might not matter for biology though!

1) There are different levels/numbers of i-motifs identified depending on the cell cycle position (highest at G1/S boundary, although this is only comparing cells synchronized to G1, G1/S and early S so maybe more at different points?), suggesting these structures don't just stably form and then just sit happily around for the entire lifetime of the cell.

2) In vitro these motifs are less stable than (say) G-quadruplexes so presumably there is a suggestion they may be transient over short timescales, but this is not actually examined in the paper. No idea how you'd actually test this without inherently perturbing the equilibrium being examined in vivo. Even if you could avoid fixing the cells antibodies would be out of the question because of the inherent linkage (if you bind the i-motif with a 500 pM Kd [high affinity] you're gonna HUGELY stabilize that conformation).

Ah - this is very good point, thanks for following up on this!

I did feel awkward writing it - in this case it was actually meant sincerely. I really wasn't sure if I'd misunderstood. It seemed too ironic in a discussion on open minded-ness to basically say "I immediately stopped listening after I heard something I didn't like" (although maybe this is a reasonable approach? I'd strongly argue it's not, but that's certainly a discussion we can have). I'll do my best to catch myself in the future. I should say that I did read your comment as a touch condescending, just FYI.

WRT to Dunning-Kruger for open-mindedness (which is a very interesting idea) some quick searches didn't reveal anything obvious, but I may be using the wrong keywords - social psychology isn't exactly my strong suit! Sort of intuitively you'd think a similar kind of relationship might exist ("Of course I'm open minded, but I _know_ that X is X and Y is Y, but those are truths not debatable ideas!") - although maybe now I'm conflating open mindedness with the ability to think critically...

If the fact that you disagrees with the first clause in an argument is enough for you to conclude the rest of the discussion is unable to make you change your opinion, I'd argue that is a much more significant barrier to open dialogue.

And why we see fields like law being dominated by women, right?

EDIT: I, and I suspect most other scientists wouldn't disagree that there are [edit - had this as aren't previously, woops!] physiological differences between men and women, but as I read the memo, that was not what was being argued. What was being argued was that those differences were the reason for the gender imbalance in tech (i.e. women are predisposition to be less interested/capable in STEM fields), in other words, the effect size associated with biological sex is larger (and indeed must be significantly larger) than any/all combined societal/'nurture' effects.

That said, here are several at least semi-relevant papers that have influenced my thinking on a bunch of things (no particular order).

[1] Wheeler, L.C., Lim, S.A., Marqusee, S., and Harms, M.J. (2016). The thermostability and specificity of ancient proteins. Curr. Opin. Struct. Biol. 38, 37–43. (Probably paywalled but available on the Harms' lab website - https://harmslab.uoregon.edu/publications/. Mike's work on thinking about the biophysics of evolution is in general super cool. Similarly work by Adrian Serohijos is really interesting, although I am in general less familiar with it http://www.serohijoslab.org/publications.html)

[2] Tikhonov, M. (2016). Community-level cohesion without cooperation. Elife 5. (Open Access, really cool, and publishing a single-author original paper in a top journal in this day-and-age is incredibly impressive).

[3] Riback, J.A., Katanski, C.D., Kear-Scott, J.L., Pilipenko, E.V., Rojek, A.E., Sosnick, T.R., and Drummond, D.A. (2017). Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned Response. Cell 168, 1028–1040.e19. (Paywalled, but IMO a HUGELY important study for thinking about 'aggregation' in the context of cellular fitness)

[4] Chakrabortee, S., Byers, J.S., Jones, S., Garcia, D.M., Bhullar, B., Chang, A., She, R., Lee, L., Fremin, B., Lindquist, S., et al. (2016). Intrinsically Disordered Proteins Drive Emergence and Inheritance of Biological Traits. Cell 167, 369–381.e12. (Paywalled, but potentially one of the most important discoveries in cellular adaptation in decades. More work to be done though!)

[5] Halabi, N., Rivoire, O., Leibler, S., and Ranganathan, R. (2009). Protein sectors: evolutionary units of three-dimensional structure. Cell 138, 774–786. (Paywalled, but super important for thinking about the relationship between local structural coupling and evolutionary behaviour. In general, everything Rama puts out is just gold.)

FWIW, this is the submission to my committee, so I'm now spending the next few weeks meticulously going through to tighten up the grammar, catch typos etc., before it gets officially submitted in June.

We wish to understand mechanism through the elucidation of design principles, yet evolution does not select for principles, it selects for fitness, an epistatic and emergent property. If similar outcomes can be achieved in different but equivalently fit ways, then given the stochastic nature of evolution this is almost guaranteed to happen. We have specific examples where every statement in the preceding paragraph is true [ed: a collection of proposed mechanisms]. We do not need one person to be right or wrong; our nascent understanding of complex biological systems is that the space of information-processing solutions is astronomical. Think of the diversity observed in structural biology - the repertoire of tertiary structures is enormous. There are countless examples of nearly identical functions being performed by proteins with radically different structure.

This divergence, this variety in structure and function, is what makes evolution robust. It is an inherent bet-hedging mechanism woven into the fabric of statistical physics. On the contrary, the desire to categories and abstract complexity into distinct groups is an inherently human endeavour. Much as we may wish and as convenient as it would be, Nature does not have a plan.

People used to (very reasonably) assume that 'disordered' just meant totally random, so the thought was these disordered proteins behaved like a random polymer. However, just like in folded proteins, the amino acid sequence of these IDPs has a major impact on the way these clouds of conformations behave. Happy to discuss more here or 'offline' (see my profile for contact info) - this is basically my whole PhD, so, you know, I can go more in depth...

We have some cool stuff coming along...

FitBit's customer service with me has been nothing but exceptional from start to finish, and is the reason I have bought several for family members.

I would hope that FitBit would recognize the loyalty they create based on this quality of service could be magnified by grandfathering Pebble's various services and by maintaining them, while helping Pebble users to transition at their convenience. This would allow Pebble users to continue to have functioning Pebble watches, with the likelihood of sticking with FitBit once the watch does finally break.

http://holehouse.org/mlclass/

- You'd want it to be somewhere isolated to avoid casualties, especially if there was a radiation risk (which you wouldn't know).

- You wouldn't want people to be able to analyze the immediate wreckage with any kind of high fidelity because there might be signatures of whatever you sent back (or however you sent it) that might change the course of history/technology.

- You'd want there to be fairly detailed recordings (ideally photos), and for it to persist into modern history, not just be a weird anomaly of 'the past'.

- You wouldn't want it be interpreted as some kind of military action.

To be very clear, I don't actually believe this is what happened, but I quite like the idea...

[1] Holehouse, A. S. & Naegle, K. M. Reproducible Analysis of Post-Translational Modifications in Proteomes-Application to Human Mutations. PLoS One 10, e0144692 (2015). (http://journals.plos.org/plosone/article?id=10.1371/journal....)

As far as I know, sporadic CWD is relatively uncommon, but given CWD is caused by the PrP protein, and there are a number of known mutations in PrP which can increase its likelihood of undergoing prion-conversion, I'd hope they're going to sequence this animal's PrP gene to see it it shed's some light on the etiology.

Irrespective, this could still mean that CWD is now endemic in Europe.

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Updated for clarity and extra info/context (thanks pbhjpbhj!)

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CWD: Chronic Wasting Disease (deer-based prion disease - main topic of article)

PrP: The specific prion protein involved here. Note that (confusingly!) prions are both a 'class' of proteins but also refers to a specific protein (PrP).

Prions (class) are proteins which can exist in one of two states. In their soluble form they're happy-go-lucky proteins that are monomeric (i.e. exist as a single unit). However, these soluble-form prions can undergo a conformational change (re-arrange their shape) into a different conformation (the infectious form). The infectious form of the prion can do two specific things: 1) Aggregate (so all the previous soluble prion proteins get stuck into a big wad of protein) 2): Catalyze the conversion of soluble-form prion into the infectious form. Herein lies their infectivity - you get an exponential growth in the number of proteins in the infectious state.

Prions (PrP) is a specific protein found in many higher-order multicellular organisms that is the SPECIFIC protein that causes a range of prion diseases (Creutzfeldt-Jakob Disease (CJD), BSE [mad cow], CWD, Scrapie etc). There are species barriers to these diseases, even though the proteins are pretty similar (i.e. humans cannot catch CWD from deer, even though the PrP protein misfolds in CWD and the same human version misfolds in CJD). These species barriers are convenient (!!) but very poorly understood, which is somewhat concerning.

Finally - it's worth point out prions aren't always bad. Fungi use them as a mechanism to facilitate non-genetic heritability/diversity [1], and we're increasingly finding examples of prion-like mechanisms that facilitate fast and irreversible signalling in cells (e.g. in the inflammation response [2])

[1] True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).

[2] Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207–1222 (2014).

1) People who are susceptible to vCJD are more susceptible to AD

2) The (cellular) stress caused by vCJD increases susceptibility for AD

3) People who have had brain surgery (a traumatic and stressful experience in terms of brain swelling) are more susceptible to AD

All three of which would be entirely inline with the fields' current way of thinking about AD, proteostasis, CBI etc. Which is not to say I actually don't think that there is a transmissible element, but I think we should avoid jumping to conclusions...

Historically and practically, biology as a field has often represented processes and events in an highly linearized and well defined fashion. This is extremely attractive for a number of reasons. As one key example, we (as humans) remember through narrative, and so the construction of a Rube Goldberg type description of a process is often a useful technique for easy recall of complicated information ("A hits B which winds up C and switches on D etc...").

The other reason is that many of the experiments would really imply a linear pathway if that were all one look for. There is often a clear-cut progression of information signals or metabolic intermediates moving from one state to another state through well defined intermediates, such that if that were what you were looking for, you'd find it.

In this representation, many biological processes are highly analogous to computer programs which perform some task - you have an input, and through functional manipulation generate an output.

The realty, as has been uncovered in the last 15-20 years, is that most of these processes and events are not linear pathways. They are wildly heterogenous networks that integrate information spanning a range of temporal and spatial scales. The non-equilibrium nature of the cell means that, to a certain extent, everything is coupled to everything else through interactions where the associated coupling coefficients are also dependent on everything else.

The reason I bring this up is that I think it's very temping to find analogies between CS and biology (DNA = hard drive, RNA = memory etc). The problem with this is that we (again, as humans) implemented the underlying computer architecture, while we're only scratching the surface of biological complexity. By prescribing that some mapping of CS-to-biology exists we risk convincing ourselves that we understand the biology better than we do, or making assumptions regarding how the biology may or may not work.

Clearly, this kind of description can be used early on, but its important to recognize that these analogies should be viewed as broad-brush stroke descriptors and not functional ones.

[1] J. Gardner, M. Kusner, Z. Xu, K. Weinberger, and J. Cunningham, in Proceedings of the 31st International Conference on Machine Learning (ICML-14) (JMLR Workshop and Conference Proceedings, 2014), p. 937

That said, hopefully it's all new to [some] other people!

Edit: Just for transparency (topical!) I did not downvote you, and totally agree that cronyism is a major (and yeah maybe causative) issue, but I also think the decision on how to fund is basically an entirely separate problem which really doesn't have an obviously good solution (in my mind).