Dear Artem, Tom, Janet, for me and probably others the usage of words like 'magic bullet' (which you defend, or try to redefine) implies a belief-based esoteric approach that has little to do with science. I suggest that to obtain funding, 'magic bullets' should not be promised, because these cannot be delivered (I gave the lo-gravity hi-funding example).
That this discussion (including messages by Janet and Tom) happens at all suggests that crystallization is currently not a science - it lacks a consistent nomenclature and way of documentation, and suffers from strong publication bias (many unpublished negative results). On the other hand, what you (Janet, Tom) write about the research that should/could be performed - this sounds a lot like a scientific approach, and is not different from what has been realized in other areas of crystallography. Yes, existing tools for predicting crystallization success are not consulted because the rate of false positives and false negatives is high. If those rates could be reproducibly reduced, I bet the usage would go up - that could start a feedback loop leading to even better predictions. Is work in this direction sexy? No. Is it useful? Yes. Is it hard work? Yes. Does it contribute to make crystallization a science? Yes. What about 'deep learning' applied to crystallization outcomes? Can it guide individual trials better than intuition? Can it find previously unknown promising combinations on a larger scale? Can this be funded? Yes of course. Your statement that crystallization gets no funding may be true in some countries (but aren't CCP4BB readers from the U.S. also reviewers?), but it's untrue in others - think of groups in France that obviously got long-term funding. And for space (low-gravity) - that amount of funding could have been used for a lot of meaningful earth-bound research. Kay Am 21.07.19 um 23:04 schrieb Artem Evdokimov: > Dear Kay > > > I disagree that 'magic bullet' is impossible. I think the definition is wrong > here - magic bullet to me is a rational set of methods that (when executed > with precision and care) enable crystallization to the maximum possible > benefit. This includes everything - constructs, crystallization design, etc. > Part of the magic bullet is also a precise knowledge when crystallization is > unlikely (i.e. an actual proven predictor that consistently discriminates > between "you're going to succeed if you work hard" and "it's doomed to fail, > don't bother" scenarios in crystallization. > > The above is not sexy. It does not present itself as a lovely subject on > which to have international cocktail parties with politicians delivering > fancy speeches. But that is what is needed, and no one is funding that to the > best of my knowledge. > > What needs to be done is a significant amount of testing, standardization, > and methods development from the perspective of holistic outcome (i.e. > crystals that work) - and none of the previously advertised 'magic bullets' > work the way I just described. > > Having written this, I think you're right - this is a bit of a distraction > from James' original point. However it's a valid opportunity for a lively > discussion on its own :) > > Artem > > - Cosmic Cats approve of this message > > > On Sun, Jul 21, 2019 at 4:52 PM Kay Diederichs > <kay.diederi...@uni-konstanz.de <mailto:kay.diederi...@uni-konstanz.de>> > wrote: > > Dear Artem, > > black or white is not my way of thinking, which is why I don't believe in > Hannibal's approach when it comes to crystallization. > > None of the magic bullets that were advertised over the past decades have > proven generally applicable. I believe more in incremental improvement which > in this case includes a few biophysical characterization methods, possibly > improved microfluidics or other apparatus, and expanded screens. And a lot of > hard work, perseverance, intuition, frustration > tolerance. Nothing that really needs huge funding - of course it does > need money, but just a share of what is anyway needed for the usual lab work > including expression, purification, functional characterization, binding > studies and the like. > > One area where a huge amount of money was burnt is crystallization in > space, on board of e.g. the spacelab and ISS. This is for me an example of a > mis-led approach to throw money at a difficult problem, with the expectation > of a solution. Science does not work like that, and money in this case seems > more to be the problem than the solution. > > This example may illustrate a certain failure of us scientists to resist > the temptation to promise unrealistic outcomes when confronted with money > provided for political reasons, which ultimately undermines our credibility. > But this takes us away from James' points. > > best, > > Kay > > On Sun, 21 Jul 2019 16:06:48 -0400, Artem Evdokimov > <artem.evdoki...@gmail.com <mailto:artem.evdoki...@gmail.com>> wrote: > > >Dear Kay, > > > >Even the small, badly diffracting and 'messed up' crystals are still > >crystals. There is literally a phase transition (pun very much intended) > >between growing *usable crystals* versus *having no crystals* (or having > >crystals that do not qualify as 'diffraction quality' even under the most > >favorable light). Points 2-9 fall into the 'I have crystals' bucket and > >everything else is in the 'I have no crystals' bucket. > > > >I am being deliberately black and white of course. > > > >As to whether huge funding would help to bridge the 'phase gap' - to me > >this is a purely theoretical question since to the best of my knowledge > >there never was a 'huge funding' for this particular problem :) And if it > >is true that the general belief in the art is that crystallization is not > >worth investing into because there's no hope in it then of course it is a > >self-fulfilling prophesy. > > > >There is an unresolved dichotomy buried in the sentiment above: it seems > >that we (the community of structural biologists) more or less believe > that > >crystallization research is not fundamentally fruitful (hence the > >no-funding situation). However, anyone who undertakes significant efforts > >to determine an actual structure using crystallography inevitably *has > to* > >crystallize their target of interest - and therefore by definition has > hope > >that their particular target will work out, against the overall gloomy > >outlook on the crystallization science as a whole. So we either are a > >collective of self-induced schizophrenics, or the general sentiment is > >wrong and systematic crystallization research is meaningful and > >fruitful - *just > >very very hard*. > > > >In ~200 BC Hannibal reportedly said "I will find a way or make one". I > >think that if we approach problem #1 with this attitude (and an > equivalent > >of a very large army's worth in funding) then it can be solved. > > > >Artem > > > >- Cosmic Cats approve of this message > > > > > >On Sun, Jul 21, 2019 at 1:55 PM Kay Diederichs < > >kay.diederi...@uni-konstanz.de <mailto:kay.diederi...@uni-konstanz.de>> > wrote: > > > >> Hi Artem, > >> > >> you are certainly correct in that James' points 2-9 would be moot if > his > >> point 1 were solved. But as long as this is not the case, we resort to > work > >> with few and/or small and/or badly diffracting and/or non-isomorphous > >> crystals, which makes points 2-9 very relevant. > >> > >> Maybe the reason why crystallization research is not well funded is > that > >> it is not expected to yield significant improvements. Personally, I > think > >> that even huge funding would not result in methods that succeed in > >> crystallizing all molecules. > >> > >> best, > >> Kay > >> > >> On Sun, 21 Jul 2019 11:28:14 -0400, Artem Evdokimov < > >> artem.evdoki...@gmail.com <mailto:artem.evdoki...@gmail.com>> wrote: > >> > >> >Excellent question :) > >> > > >> >First of all, thank you for putting this out to the community! > >> > > >> >Secondly, I agree with several of us who've written that a single > >> >conference is not enough to discuss all the possible topics. > >> > > >> >Thirdly, in my opinion all the other problems are secondary to the > main > >> >(and only remaining!) problem in crystallography: getting > >> >diffraction-quality protein crystals reproducibly and quickly > >> > > >> >The amount of funding for serious crystallization research seems to be > >> >close to non-existent. In general methodology funding is hard to get, > but > >> >crystallization seems to me like the absolute underdog of the method > pool > >> - > >> >the true 'red headed stepchild' of the methods development funders. > >> > > >> >At risk of repeating myself - the other problems (worthy, > significant, and > >> >urgent as they are!) are subservient to the main issue at hand - > namely > >> >that crystallization remains an unpredictable and artful phenomenon > while > >> >literally all other aspects of structure determination process (the > gene > >> to > >> >structure pipeline, whatever you might call it)have made astronomic > leaps > >> >forward. > >> > > >> >Artem > >> >- Cosmic Cats approve of this message > >> > > >> > > >> >On Mon, Jul 15, 2019 at 3:44 PM Holton, James M < > >> >0000270165b9f4cf-dmarc-requ...@jiscmail.ac.uk > <mailto:0000270165b9f4cf-dmarc-requ...@jiscmail.ac.uk>> wrote: > >> > > >> >> Hello folks, > >> >> > >> >> I have the distinct honor of chairing the next Gordon Research > >> >> Conference on Diffraction Methods in Structural Biology (July 26-31 > >> >> 2020). This meeting will focus on the biggest challenges currently > >> >> faced by structural biologists, and I mean actual real-world > >> >> challenges. As much as possible, these challenges will take the > form of > >> >> friendly competitions with defined parameters, data, a scoring > system, > >> >> and "winners", to be established along with other unpublished > results > >> >> only at the meeting, as is tradition at GRCs. > >> >> > >> >> But what are the principle challenges in biological structure > >> >> determination today? I of course have my own ideas, but I feel > like I'm > >> >> forgetting something. Obvious choices are: > >> >> 1) getting crystals to diffract better > >> >> 2) building models into low-resolution maps (after failing at #1) > >> >> 3) telling if a ligand is really there or not > >> >> 4) the phase problem (dealing with weak signal, twinning and > >> >> pseudotranslation) > >> >> 5) what does "resolution" really mean? > >> >> 6) why are macromolecular R factors so much higher than > small-molecule > >> >> ones? > >> >> 7) what is the best way to process serial crystallography data? > >> >> 8) how should one deal with non-isomorphism in multi-crystal > methods? > >> >> 9) what is the "structure" of something that won't sit still? > >> >> > >> >> What am I missing? Is industry facing different problems than > >> >> academics? Are there specific challenges facing electron-based > >> >> techniques? If so, could the combined strength of all the world's > >> >> methods developers solve them? I'm interested in hearing the voice > of > >> >> this community. On or off-list is fine. > >> >> > >> >> -James Holton > >> >> MAD Scientist > >> >> > >> >> > >> >> > ######################################################################## > >> >> > >> >> To unsubscribe from the CCP4BB list, click the following link: > >> >> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 > >> >> > >> > > >> > >######################################################################## > >> > > >> >To unsubscribe from the CCP4BB list, click the following link: > >> >https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 > >> > > >> > >> > ######################################################################## > >> > >> To unsubscribe from the CCP4BB list, click the following link: > >> https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 > >> > > > >######################################################################## > > > >To unsubscribe from the CCP4BB list, click the following link: > >https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1 > > > ######################################################################## To unsubscribe from the CCP4BB list, click the following link: https://www.jiscmail.ac.uk/cgi-bin/webadmin?SUBED1=CCP4BB&A=1
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