Dear James, Here you go, a “grand challenge” suggestion to consider for funding from the “James Holton Foundation for structural biology research”:- “The human genome/proteome in 3-D” Greetings, John Emeritus Professor John R Helliwell DSc
> On 14 Sep 2019, at 02:39, James Holton <jmhol...@lbl.gov> wrote: > > > I would like to thank everyone who took the time to respond to my question > that started this thread. It is really good for me to get a sense of the > community perspective. Some debates were predictable, others not. Many > ideas I agree with, some not so much. All were thought-provoking. I think > this is going to be a really good GRC! > > Something I did not expect to distill from all the responses is that the > dominant challenge in structural biology is financial. The most common > strategy suggested for addressing this challenge was torpedoing other > scientists in similar fields, perhaps expecting to benefit from the flotsam. > Historically, this strategy is often counterproductive and at best > inefficient. The good news is there is a lot of room for improvement. In > reality, we are all on the same ship, and the people in our funding agencies > fighting to get us what we need can be much more effective when armed with > positive ideas and clear plans. That is a better strategy for overcoming > this challenge. > > To this end, my first GRC session title is going to be: > > "If I had a trillion dollars for structural biology" > > I think we can all agree that science in general is vastly under-funded > relative to the impact it has on the human condition. For example, I > estimate the value of a general cure for cancer to be at least a trillion > dollars. This is based on the lives claimed every year, multiplied by how > much one person would gladly pay after being diagnosed (amortized over the > rest of their much longer life). This is only ~1% of the Gross World Product, > a real bargain if we can come up with a plan that will actually work. > > Now, obviously not all cancer research is structural biology, but not all > structural biology is cancer research either. Let us suppose for a moment > that you (yes, I'm talking to YOU), were given a trillion-dollar budget to do > your science. After buying all the tools and hiring all the people you > wanted: would that solve all of your problems? I expect not. The > intellectual and technical challenges that remain are what I believe science > is really all about, and the 2020 Diffraction Methods GRC will focus on the > ones facing structural biology. > > My goals here are twofold: > 1) I believe it would be healthy for this field if we all spent a little time > "thinking big" > 2) I want to remove financial anxiety from the discussion, both here and at > the GRC. > > I ask for one restraint: please confine the discussion to structural biology. > I understand it is difficult to think about the trillion-dollar level > without involving politics, but the CCP4 Bulletin Board is not a political > discussion forum, and neither is the GRC. Assume all the other worthy causes > in the world are given their own ample budgets. This trillion is yours, and > you have to spend it on structural biology. If you can't think of anything, > think harder. > > To get you started, a few things that could be done for under a trillion > dollars: > 1) re-do all the protein crystallization in the PDB, 500 times (saving all > information) > 2) buy Google and Facebook, get their AI teams to do machine learning and > structure prediction for us > 3) hire every "biological scientist" in the world, and give each $1M to work > on your projects > 4) re-do the NASA Apollo program three times > 5) build 1000 XFELs and 100,000 Titan microscopes (yes, that's "and") > 6) solve the phase problem by brute force. (zettaflops-scale computing at > $0.03/gflop) > 7) build half a dozen terapixel detectors (ask Colin Nave what those can do) > 8) fund every NIH grant submitted in the last 5 years. Not just the awarded > ones, all of them. > 9) X-prize style competitions for landmark achievements, such as predicting > crystallization outcomes, or finding a universal way to stop protein from > denaturing on the air-water interface. > > This is not a to-do list, but rather an attempt to convey the scale of what > can be done. Oh, and you have a month or so to think about it. The meeting > is July 26-31 2020, but my speaker list is due Oct 15. > > Now, of course, at the GRC I will not actually have billion-dollar prizes to > pass around, but I do want to set our sights on those lofty goals, and then > work on the bridge we will need to get there. > > So, when I say "challenge" I mean more than something we all agree is hard. > Those would make for very short talks. I am after something more like a > benchmark. Useful challenges should have certain properties. They should be: > a) possible, because something that doesn't work no matter what you do is no > fun. > b) hard, because something that is too easy is also not very interesting > c) realistic, as in relevant to a real-world problem we all agree is important > d) accessible, as in reasonable download sizes and/or affordable reagents > e) fast, because it if takes forever to try it nobody will have time to > participate > f) measurable, as in having a clear and broadly acceptable "score" > g) adjustable, as in the level of "difficulty" can be selected continuously > between "easy" and "impossible". > > This last one is important because it is at the transition point between > success and failure that teaches us the most about what can be improved. > > Some challenges that already exist are: > anomalous phasing from weak signals > https://bl831.als.lbl.gov/~jamesh/challenge/anom/ > anomalous phasing from twinned data > https://bl831.als.lbl.gov/~jamesh/challenge/twin/ > merging highly incomplete data with an indexing ambiguity > https://bl831.als.lbl.gov/~jamesh/challenge/microfocus/ > extracting motions from diffuse scatter data > https://bl831.als.lbl.gov/~jamesh/challenge/diffuse/ > Coming soon: > dial-a-resolution model building challenge > XFEL data processing reference set > > -James Holton > MAD Scientist > >> On 7/25/2019 10:07 AM, Keller, Jacob wrote: >> >>It would seem to me that an important issue is also: do get all >> >>information out of our diffraction data? By integrating the Bragg peaks we >> >>usually neglect the diffuse scattering that could potentially contain >> >>additional (dynamic) structural information. This can be cloudy diffuse >> >>scattering hidden in the background but also diffuse streaks that contain >> >>information on packing disorder and reveals intrinsic interactions in the >> >>crystal. >> >> Along these lines, and taking a page from you also, how about >> “crystallographic model refinement as image-faking?” Metrics of the goodness >> of a particular refinement could simply be some measure of the correlation >> between predicted vs. measured images. I have seen some of this done with >> diffuse scattering, but why not with the whole thing, including intensity >> and shape of Bragg peaks, solvent rings, etc? Maybe instead of doing the >> multiple steps of (indexing, integration, scaling, solving…) all of this >> could be refined as one? Processing parameters like moscaicity [sic] etc >> would now be part of the final model…? >> >> JPK >> >> >> >> >> Loes Kroon-Batenburg >> >> On 07/15/19 21:44, Holton, James M 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 >> >> >> >> -- >> >> __________________________________________ >> >> Dr. Loes Kroon-Batenburg >> Dept. of Crystal and Structural Chemistry >> Bijvoet Center for Biomolecular Research >> Utrecht University >> Padualaan 8, 3584 CH Utrecht >> The Netherlands >> >> E-mail : l.m.j.kroon-batenb...@uu.nl >> phone : +31-30-2532865 >> fax : +31-30-2533940 >> __________________________________________ >> >> 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
