Raw Data in Organic Chemistry Papers/Open Science

Open science is a way of conducting science where anyone can participate and all ideas and data are freely available. It’s a sensational idea for speeding up research. We’re starting to see big projects in several fields around the world, showing the value of opening up the scientific process. We’re doing it, and are on the verge of starting up something in open source drug discovery. The process brings up an important question.

I’m an organic chemist. If I want people to get involved and share data in my field I have to think about how to best share those data. I’m on the board of more than one chemistry journal that is thinking about this right now, in terms of whether to allow/encourage authors to deposit data with their papers. Rather than my formulating recommendations for how we should share chemical data, I wanted to throw the issue open, since there are some excellent chemistry bloggers out there in my field who may already have well-founded opinions in this area. Yes, I’m talking about you.

The standard practice in many good organic chemistry journals is not to share raw data, but typically to ask for PDF versions of important spectra, usually for novel compounds. These naturally serve as a useful tool for the peer-review process, in that a reviewer can easily see whether a compound has been made, and say something of its purity. Such reproductions are not ironclad guarantees that a compound has actually been synthesised, nor that it was the reported process that actually gave rise to that sample. Nonetheless, it’s useful to the reviewer.

Are PDF reproductions useful to science? Well, not really. Peter Murray-Rust talks about PDFs as being “hamburgers”. I think I understand what he means: PDF data are dead – actually very dead, and the cow would be more interesting. You can’t DO anything with a pdf. You can’t take the data and do anything with them. Nobody can re-analyse the spectrum, or zoom in. The spectrum can’t be understood by a machine with any accuracy. Data are lost in conversion.

With raw data, you allow other people to check the data. You also allow them to re-analyze. You allow computers to take the data and do interesting things. If all data were raw, you could ask the interweb, for example, “Find me examples of compounds containing an AB quartet with a coupling constant above 18 Hz. And the molecule needs to contain nitrogen. And synthesized since 1987. And have a melting point.” Maybe that question’s important, maybe not. But with raw data you can at least ask questions of the data.

What are the downsides of posting raw data in organic chemistry, either in papers or to lab book posts:

1) You have to save the data and then upload them. Well, this was a problem in 1995, but not now.

2) The data files are large. Not really. A 1H NMR spectrum is ca. 200KB.

3) It’s a pain. Yes, a little. But we must suffer for things we love.

4) People might find mistakes in my spectra/assignments. Yes. You’re a scientist. This is a Good Thing.

An important fact: For many papers, supporting information is actually public domain, not behind a paywall along with the rest of the paper. The ACS, for example, would, by posting raw data as SI, allow the free exchange of raw spectroscopic data. That would be neat.

I wouldn’t advocate stopping PDF reproductions, necessarily, since these are still useful for review, and for the casual reader. We’re likely to keep using PDF for our electronic lab notebooks, but the data need to be there too. Like ortep and cif – picture and data.

If we can establish that we should be posting raw data, then what kinds of data should we share, and how? This post is meant to outline an answer, and ask for feedback from anyone who’s already thought about this.

1) X-ray crystallography. This is the exception. Data are routinely deposited raw, and may be downloaded. Not always the case, but XRD blazes a trail here.

2) NMR spectroscopy. The big one. IUPAC recommends the JCAMP-DX file format. Jean-Claude Bradley has been a proponent of this format, and has demonstrated how it can be used in all kinds of applications. We’ve played with it, and in one of our recent papers we deposited all the NMR data in this format in the SI. We’ve been posting JCAMP-DX files in our online electronic lab notebooks, e.g. here. My opinion of this file format (both generating it, and reading it) has not been great. There are two formats, I understand, and we found that if we saved the data in the wrong format, we couldn’t read the data with certain programs, but could with others. i.e. we had to get the generation of the file just right. That kind of trickiness, though small, just inevitably means people won’t bother to generate or use the files on a mass scale (unless the journals decide to back it). PDF’s popularity is based on the ubiquity of the reader. JCAMP-DX works well with Jspecview, a free, open source NMR data reader. We’ve not enjoyed our experiences with this, either, though it’s a wonderful endeavour. This led us to look at whether there was a need for saving the data in a particular format, or whether we could just save the raw data, and process those data with a free piece of software. After looking at this with our resident NMR guru, Ian Luck, we found that saving raw data is easy (it’s just a copy and paste of what’s produced by the machine) and that the raw data can be read by free software such as Spinworks or ACDLabs, obviously in addition to our in-house software. This seems ideal? Does anyone have the reason IUPAC prefers a derived data format over the raw data, other than JCAMP-DX is a single file? Aren’t raw data likely to be the most generically useful long-term?

I don’t know if people have experience of this. I was in touch with one of the ACS journals recently, who indicated that their view was that the journal is not a data repository, and that posting of raw data (which was in their view to some extent desirable) should be posted elsewhere, e.g. to an institutional repository. This is an option. I think it’s less convenient. PLoS seem happy to host the data.

3) IR data. Don’t know if there is a standard. If the file is small, saving raw data could be encouraged. Would allow easy comparisons of fingerprint regions.

4) Mass spectrometry. It’s not clear to me there is a huge advantage here to sharing raw data, for a typical low res experiment?

5) HPLC data. Again, the outputs are fairly simple, and I’m not clear about the advantage of raw data (which I’m assuming would be absorbance vs. time table). Would (perhaps) permit verification that traces have not been cropped to remove pesky impurities.

6) Anything else?

I’m a Scientist Get Me Out of Here!

A week or so ago I was a contestant on the inaugural Australian version of I’m a Scientist Get me Out of Here! Scientists were gathered in an online area – 5 in each zone – and peppered with science questions by school kids. The questions could be on anything, and came in directly via the website, or during frantic real-time chat sessions where we’re really interacting with the kids. The event was recently piloted in the UK, but this was the first time it was run elsewhere.

Naturally kids have access to people with science backgrounds – their teachers, first and foremost. They can also read stuff and watch stuff on TV and read things online. But this competition gives them a chance to interact directly with practicing scientists, and that doesn’t normally happen.

After a week or so of asking questions the students start voting for which scientist they’d like to stay, and the one with the least votes is evicted. One eviction per day until the winner is declared and awarded $1000 to help fund a science outreach activity. The evictions were pretty brutal. It was interesting that many of us spent a lot of the week describing good evolutionary arguments for various things, but when you’re actually part of a survival of the fittest exercise, suddenly it’s not so great. I lasted till the final two in the Hydrogen Zone, and was pipped to the post by Aimee Parker, a Monash Honours student and budding science communicator with a flair for explaining science of all kinds. Congratulations Aimee, well deserved.

So how was it? It was a total blast. Any scientists reading this – sign up to get involved next time round.

The questions would sometimes come in late at night – one batch were released around 11 pm, and I found myself typing away for a couple of hours like some sci-junkie. The addictiveness comes from the fact that it’s a competition, sure, and you want to answer questions first so that you can get your answer in first. But it’s much more the kinds of questions you get (which are on a broad range of things) and partly because you feel that the kids actually want to know the answers. You can also wax lyrical about what science is and what you do in your work. Then you can switch to talking about relativity and GM foods.

Some highlights included an excellent question on what are the 5 commonest molecules (see how the ambiguity necessitates a long answer), a question on predicting when we’ll be eating synthetic meat, various questions about lightning, a truly awesome question about what happens if you’re in a car going at the speed of light and you switch on the headlights (needed several goes at that one)  and another priceless one that generated a lot of analysis about what it’s like at the centre of the Earth if you dug a hole there.

There were also lots of solid, sensible questions that it felt good to answer. A lot of questions were Googlable/Wikipediable, but were still asked, which may say something about children’s healthy skepticism of answers on the web, or their over-faith in the authority of scientists to talk on any subject. Interestingly there were quite a few questions (both on the website and in the furious chat sessions) about a) whether the world would end in 2012, and b) evolution/big bang/origin of life. On the first of those, it was interesting that the kids were all asking about the supposed 2012 apocalypse, but that hardly any of them believed it. So the idiotic meme was successful but did not stand up to much thought. On the other hand the questions about evolution and related things indicated that a lot of kids were wrestling with the contrast between religion and science and it wasn’t clear in many cases which way they were going. The questions were often phrased with a hint of disbelief that things could just have “arisen” or “happened” which perhaps suggested that the kids weren’t so happy with all the uncertainties of the current state of scientific origin theories. I was at pains to point out that uncertainty is good, because it makes us ask questions, and that science is about probabilities rather than absolutes. But it’s still a challenge, and it was great to be able to lay those challenges out.

Thanks to the wonderful team behind the event (Kristin, James, Sarah) for making everything work so well and adeptly fielding the hilarious curveballs that would crop up in the chats, and thank you to all the school children who asked stuff (particularly the ones who voted for me – I love you guys…) The kids made it such a cool event by virtue of their most awesome weapon – curiosity. All power to them.

Open Science Student Projects

We’re launching a new kind of student project in synthetic organic chemistry. The idea is this: any student anywhere in the world can join in, provided all data are posted openly online. We aim to publish the research with all participants.

What we’re looking for are students who can actually carry out practical experiments in a lab and upload data. This project is ideally suited to being run as part of a formal undergraduate laboratory course, but any student can join in. We’ve just started this at The University of Sydney this year – one undergraduate, Clara, is working on the project, and she will be joined by others later in semester. Our first partner to sign up is Stanford University, where lab director Charlie Cox has run the project as an option in third year undergrad lab. A few people have contacted me informally about running the project at their own universities, and we’re going to try to secure some money to help run the project in some universities in Africa.

This post opens up the project to the rest of the world. If you’re reading this, and would like to join in, then yes, you can.

The project concerns the optimization of our resolution of praziquantel. Though the route is easy to perform, and efficient, we’re looking for ways to improve the route still further to bring the cost down.

There are a number of things we can look at. We will need to set up some online forums where the project can be discussed. If you have any questions now, you can post them below, or on the Friendfeed room, or get an account on Labtrove (our open source ELN) and post things here, or tweet me, or comment on The Synaptic Leap. There’s also email, which I’m trying to discourage, but please use this if you don’t want to discuss possible involvement in the project in the open.

The relevant online lab notebooks to which you’d contribute if you took part are here.

Any student contributing data can then take part in writing the resulting research paper, which is here. Once you’ve contributed an experiment, add your name to the paper, and start making changes to the manuscript. For undergraduates this is exciting because they can take part in real research, generating new data, rather than repeating experiments with known outcomes. This way we also aim to generate a real research publication – very useful for students interested in a career in research.

Some very important points:

1. All data generated by students are to be deposited openly on the web. Please don’t take part and not share all data – no point in doing that. Use the ELN like a real lab book – don’t leave things out.

2. We’ll publish when we’ve reached a significant milestone. What that is depends on what people do, so we can decide this later.

3. Students who contribute experimental data can be authors and can edit the paper.

4. All reagents ought to be inexpensive and generally available – this is kind of the point. The starting material itself, praziquantel, is ironically not that cheap from most commercial suppliers. At the outset of the project, we can provide PZQ to labs wanting to take part – we’ll just mail you some. We’re looking for a longer-term solution to this once things get going.

5. I/my group are starting this up and, for convenience, hosting it, but we don’t own it. If other people work on this project so much they start taking it over and leading the science, that’s perfect. Leadership in open projects is fluid. Thus anyone who takes part works for the project, certainly not “for” me or my group. There is no other incentive to taking part than getting the job done and finding a route to this enantiopure drug that’s viable for scale-up.

If you’re a student who wants to take part, go hassle your lab director/PI. If you’re a lab director reading this, please consider having a cohort of students try this lab. This is a real optimization of a real process involving a real drug that affects millions of people.

Background to the science involved can be found here. There’s a pdf there that describes some of the chemistry. Essentially, though: the resolution is several steps, and each needs improvement. There’s an initial hydrolysis of the drug, synthesis of resolving agents, the resolution itself, and then the re-isolation and purification of enantiopure drug. Each step works, but needs to be better. There are lots of very nice crystalline solids throughout. We can’t use chromatography. We need inexpensive reagents, and environmentally benign solvents. We need high yields, and effective recycling strategies. And so on.

There are other examples of distributed student involvement in science. William Scott and Martin O’Donnell began a related project in 2009 called D3, and there were some papers describing this excellent work. The difference here is that our project is open, in the sense that anyone can participate and all data are freely available as they are acquired. That may make it more chaotic. It may also make it more effective. Part of the innovation here for people taking part is working that out.

It’s also fitting that this project is being launched during the International Year of Chemistry. We’re trying to use the web not just to share data, but actually to collaborate on a real research question in experimental lab science. If you’ve an interest in trying to solve this problem, you’re free to join a worldwide effort. There’s an interesting “crowdsourcing” experiment being run by the RSC that concerns measuring the pH of water worldwide. In our project we’re not asking for a measurement, we’re actually asking students to perform synthesis, but then also to think about what experiments to try next, and to help write the paper – the full gamut of aspects of a full research project. This is pretty demanding. It’s more reminiscient of the wonderful Biobricks competition, with the difference that our project here is open and web-based, rather than a competition in a specific location.

What’s the hope here? I hope that students can get excited about working together on a real research problem, and can get a taste for what a mind-bending exercise real research is – research where you’re not even sure what question to ask at the outset, let alone how to answer it. What I’m hoping for is that students can help solve an important problem as a group. I recently went to a meeting organised by a student cohort committed to lobbying universities to take part in research in tropical diseases without necessarily seeking patents and profits, UAEM. The guy then in charge of the group, Ethan Guillen, said at the start: “Students are great allies to have if you’re a professor”. Amen to that.

Sabbatical Part 1 – UCSF

I was on sabbatical from January 20th till July 12th. Half at Stanford and half at UCSF. All California.

When I was organizing the trip I asked the (now) Dean of Science at Sydney, Trevor Hambley, what a sabbatical was for. My assumption was that it was about going to a new lab, learning a new skill and building new collaborations. Interestingly, he said “the idea is to re-charge.”

Having been, and come back, I understand what he meant, and he was right. Life should be like a sabbatical. A new technique, or a new collaboration, may be useful, but what’s really important is to reconnect with why you’re doing science, in case years of local administrative duties have clouded your youthful, pristine vision.

Why was I on sabbatical? I wanted to visit two labs, one in asymmetric catalyst discovery and one in drug discovery. These labs needed to be the best in their fields. I wanted to see how catalysts and drugs are discovered. My aim was to see how much of the work is screening and how much is design. My assumption before the sabbatical was: it’s mainly screening, since we can’t design drugs or catalysts yet from first principles. If that was the case, I wanted to try to find examples of projects that, if successful, would allow more design and less screening. In the course of this search I also wanted to think about our open science work, and find people who wanted to work this way.

I’ll write about Stanford later. My hosts at UCSF were James McKerrow and Conor Caffrey. They work at the Mission Bay Campus of UCSF, which is not in the middle of the city with the rest of the campus, but is out on the east side where the old port buildings are. It’s an odd place – a beautiful set of buildings surrounded by a view of the city (north), the water (east), wasteland-then-cool Potrero Hill (south) and outskirts of the city (west). Huge tracts of land are waiting for new buildings. You can smell the sea air. It’s a great place for an apartment, if you don’t need to buy anything. I’d like to live there.

View of San Francisco from Byers Hall

Genentech Hall, next door to Byers

I was a guest in the QB3, specifically at the Sandler Center, which has a focus on finding new medicines for neglected tropical diseases, and which supports open science. I was there due to my interest in schistosomiasis. I had also heard that UCSF Mission Bay was a unusually fertile place, scientifically.

And so it was. I had a desk and an internet connection in Byers Hall with a nice view that allowed me to contemplate the stately motion of sea freight. I had to do a number of things like writing grants and papers, but in between times I was able to sit in on the McKerrow group meetings and talk to faculty and students in the building. This was pretty much perfect – it was great to talk with Andrej Sali, Brian Shoichet, Jo Derisi, Adam Renslo and others at various points, and to sit next to Joseph Mulvaney (from the SMDC) the whole time whom I must thank for being so quiet (and answering a few dumb questions I had about cheminformatics).

A few things are really unusual about Mission Bay. The groups have fluid barriers between them. It’s never clear who is working for whom, and people often seem to go to various group meetings because there are so many collaborative projects. The faculty are working on big, interesting problems together in a highly interdisciplinary way. In my experience “interdisciplinary” is a word that people try to tape over an existing department or insert into a planning document. At UCSF it really seemed to be the way people worked.

The thing that really stood out for me was the intellectual independence of the students in the McKerrow group. At group meetings they had a very good level of understanding not only of their work but also of the context of their work in the field. They really were driving their research. The students also were excellent at questioning each other in group meetings, and not leaving this up to those in charge. Perhaps this is a feature of the US, or that it’s an elite organization, or that the research is in biology, or something. Whatever, Jim seems to be fostering a group or people who are turning into proper scientists, with a high level of control over their intellectual futures. A great place to go to graduate school.

The building itself was very attractive – Byers Hall is linked to Genentech Hall by a vertiginous atrium, and there was occasionally music there, or some other event, to mix stuff up.

Looking down the atrium in Byers Hall, with music

Over the way was a Peasant’s Pies that lots of people went to, maybe for the pies, maybe for the high quality heavy wooden furniture, maybe for the free wifi. Who knows. People were clearly writing their whole theses in there.

A frequent view towards the UCSF pie shop

We also witnessed the Byers Bash, where groups of students/faculty got together in a musical competition. People made great music, with food and beer. Jim himself unleashed his inner rock star on guitar and vocals.

Jim McKerrow takes the room at the Byers Bash, UCSF

I’d never seen anything quite like this place before. Nor could I imagine seeing a communal arcade machine in an academic building in Sydney. Fishtanks flank it.

Byers Hall Entertainment

If anyone in Sydney has an old Pacman machine going spare, we can find a good home for it in my lab.

So screening vs. design? A big question with a long answer. I’ll come back to it.

SciFoo (and how about some more Science Unconferences)

I went to SciFoo this year. This is an invitation-only, 200-person event at Google HQ in Mountain View, organized by O’Reilly and Nature. I’d been invited before, only for it to clash badly with the start of the Sydney semester and the start of my teaching, cascading over me like a waterfall of incomplete handouts and practical demonstrations. Previously I’d caved. This time I didn’t and I flew to San Francisco just for the weekend. Oh man – am I glad I went.

Gathering at the Googleplex

 

48 hours at the Googleplex. An intellectual lock-in. Nobody goes home. Nobody else comes through. It’s just them – and me. We all assembled, described ourselves to the crowd in three phrases, then wrote names of sessions we wanted to lead on post-it notes and stuck them on a grid of places and times. You grab a drink, and start talking. You stop talking when you can’t perceive your own soul anymore and need to sleep. I was jetlagged with a terrible cold that made me sound like my tonsils were made of sandpaper. But no matter.

SciFoo Schedule Board

 

So this is an “unconference” – something perhaps not familiar to many mainstream scientists. There is no pre-arranged agenda. You just get people together and let them talk about whatever they want. The schedule is made on the fly and can change. People with similar interests aggregate naturally. Through random chance or curiosity people who know nothing about the content of a session will show up.

This was the most inspiring meeting I’ve ever been to. The chemical content was next to zero. The science content was, well, it was just Proper Science, as it should be. Childish, naive, reaching for the stars. A succession of things that make you go “oooh that’s nice.” It was eyewateringly exciting. The naivety could have been annoying were it not for the fact that people invited are doing work so thoroughly marinaded in cool sauce and topped with awesomes and thousands.

The key to this success is simplicity – you just get good people. Organisers Tim O’Reilly, Timo Hannay and Chris DiBona know this very well. People the world over are doing the coolness – you just have to get them together. They then mutually remind each other why they got into science in the first place – it’s like motivational autocatalysis.

The tone was set on the first evening when Larry Page, at the end of his welcoming remarks said “You know, if what you’re doing isn’t going to change the world, then maybe you should do something else.” People kept referring to this over the next 48 hours, and it’s lodged in my brain ever since, gradually working its way to the centre.

Emily Brodsky talked for ten minutes in a Lightning Talks session about why one earthquake can trigger others. David Eagleman described how he’d dropped people off a crane to determine whether bullet-time was real. Noah Hutton gave a late-night session about a film he’s making on the Blue Brain Project, an attempt by Henry Markram to model a human brain in a computer in the next five years. Peter Singer caused a lot of discussion with his website that attempts to motivate people to donate money to charity. And so on and so on. The frustrating thing is not being able to go to all the parallel sessions. I still regret missing Yves Rossy talk about jet-propelling himself over the Channel.

The challenge when you’re there is to be able to explain how what you’re doing is going to change the world. It makes you think about your own work, and the work of the people around you. You’ve been invited because someone important (it’s never clear who) thinks that what you’re doing might well change the world. This forces you to forget about the detail we so often talk about, take a huge step back and confront the big picture lurking somewhere around you. Often at specialist science meetings, when challenged to talk about your work you might say “Well, I’m working in a calixarene-based sensor for [insert molecule]” or “I’m trying to make grantotoxin faster than this other guy” or “I do sesquiterpenes.” Technical, small answers to a technical crowd. That won’t do at a meeting like this.

On the first evening I was having a drink with a guy and Sergei Brin sidles up and asks me what I work on. My answer piqued his interest because I said “We’re working on making a drug needed in Africa by doing the science in the open, on the web, so that everyone can help us out and make the science go faster”. I got a lot of practice at permuting this kind of answer over the course of the next 50 times I was asked it. Everyone I spoke to liked the answer. Some people are doing similar things, like the truly wonderful Galaxyzoo project – their lead tech guy Arfon Smith was present. It was great to meet Michael Nielsen who made me aware that someone had already framed the concept of cognitive surplus – I’d been thinking about this ever since watching people play Tetris on their phones on Sydney buses and wishing that level of sustained concentration couldn’t be directed to a more meaningful goal.

I’ll never forget the first session. A few of us gathered in a room. I was sitting next to Will Noel, a guy putting ancient manuscripts online for the Walters Art Museum in Baltimore. The session was on “The Future of Space Travel”. An unassuming guy led it (can’t find who), and nobody was quite sure what to expect. He began by saying “So when I was flying the space shuttle…” and the room kind of changed – we all became little kids wanting to know what that was like.

It was a real pleasure to meet Derek Lowe at this meeting. Derek is a bellweather of pharma, and organic chemistry quite generally. A wise, considerate and articulate guy with a huge range of interests. We attended a session together where Lee Smolin explained what quantum gravity was. Waves (or particles) of Physics Envy crashed into me (again). Such big problems, concerning the nature of reality. Derek and I co-hosted a session on the possibility of Open Source Drug Discovery. A fascinating hour. I was able to brief everyone on what we are doing at the Synaptic Leap, where we’re trying to show we can open source process chemistry. The discussion turned to the rest of the drug discovery process, enormously facilitated by Derek’s wide-ranging expertise. The people in the room, from Creative Commons, from the White House, from industry were quick to clarify the thorny issues – but they all seemed to want the idea of OSDD to work – they all acknowledged something radical had to change in the coming years.  I’ll have to return to this in a future post but the session was so inspiring. (I seem to share a lot of interests with Esther Dyson, who was in a lot of the sessions I went to. She was able to ask the best disruptive questions whilst spending most of the time apparently approving/rejecting friends on Facebook. Whatever works…)

Derek Lowe (centre) discusses quantum gravity with Lee Smolin (right)

 

Scifoo made me think about chemistry conferences a lot. I’ve been to a large number of chemistry conferences. I went to the American Chemical Society (ACS) meeting in San Francisco in March this year. I was at the conference venue the whole time the conference was on. I didn’t speak since I missed the abstract submission deadline that was sometime back in 1998 I think. I sat in sessions the whole time, I mingled and met all the people I wanted to, as well as a few people I hadn’t expected to. I had beer at the poster session and beers with people in the evenings. Was this conference a good use of my time? Apart some excellent beer conversations, not really.

There’s a separate post that’s needed here about where organic chemistry is, and where it’s going – a few people have been posting on this recently. But just in terms of the ACS meeting itself: with a few very notable exceptions the talks I saw were a) presented in a dull Powerpoint-heavy series of slides with verbal commentary about what was on the slides where even the presenter was visibly bored with what they were saying and b) on published material that was c) way too predictable and incremental. So both the presentational style and the content were disappointing. So many talks at the ACS would have been more interesting if the speaker had simply given out paper copies of their latest paper and given us 10 minutes to read it in silence then 10 minutes to talk about it. Now of course specialism necessitates incrementalism in content, but it’s no good if the meeting becomes a chore to sit and listen to. Nor is it good if the talks come out of the Powerpoint Machine (the genius of the “Chicken Talk” is that you can kind of follow the talk structure without listening to the content – it sounds exactly like most academic talks right up to the last supplementary slide in response to the second question at the end). In maybe 80% of the talks I attended nobody asked questions, or nobody was allowed to, or people asked “pity questions” just to break the awkward silence, but which were in no way interesting in themselves. So, constructive solutions:

1) people should be excited about what they’re presenting (there were a few excellent talks at the ACS I should add, by both faculty and students). If they’re not excited, they should sit back down.

2) conferences with little slots for questions, or where there are no questions, are of no real interest at all (particularly now that you can just listen to the talks online – a great move by the ACS)

3) how about we just scrap the schedule and allow people to talk on whatever they want on the day. Sessions have a title, which is a question or a hypothesis, and people come to discuss that without any pre-made slides. This removes the inanity of talks entitled “Recent Developments in X”

The ACS can deal with 2) and 3), not 1). While considering this, you may want to examine this picture of the control panel on the Google toilet cubicle wall.

Google toilet control panel

 

and maybe this shot of the Google campus

Googleplex

 

Unconferences are the way forward. I hear that the Burning Man can be like this too (though from a look at the WP page it’s now huge). As can Maker Faire. So who’s on for a chemistry unconference, or maybe a chemistry/biology or chemistry/physics or chemistry/software unconference? (Gregynog and Gordon Conferences are close, but not quite there). Get good people together for a weekend. If you don’t want to actively participate, go somewhere else. Screw the usual formalities and just allow the day to pan out. There are no conference proceedings, and since you don’t actually present a series of slides, there’s nothing to put on your CV. Let the people who want to talk, talk, and see how the sessions define themselves, while insisting that sessions are framed around hypotheses. I wonder what would happen. Let’s try it. Sydney or London or New York or someplace nice.

The Ostrom Rules and Online Projects

Sydney Uni has an enlightened organisation within it called CHAST that organises science talks of wide general public interest. We recently hosted David Sloan Wilson who spoke on “Evolving the city: using evolution to understand and improve the human condition“. The talk touched on a number of cool ideas. At the end he spoke of self-organising social systems – that often social groups can run very efficiently without the need for excessive top-down regulation. In order for this to work there needed to be certain rules to prevent a system from using up its natural resources and withering. This is a biological argument that he was applying to a social network, such as a city neighbourhood. He referred to Elinor Ostrom‘s 8 principles for resource management. There need to be:

1. Rules

2. Reward systems

3. Collective choice arrangements

4. Ways to monitor the system (by people who are involved or who have a stake)

5. Graduated sanctions for bad behaviour

6. Mechanisms for conflict resolution

7. Rights to self-organise recognised by a higher authority (not God, people)

8. Scalabilities – the rules above need to apply also to the relationship between groups

As I was listening I thought – “These are excellent principles for the operation of any open source project”. I’ve been thinking how to carry out research projects in the open (such as these ones), and how to write papers (such as this one that’s in progress). The Polymath project sought rules for good behaviour which seemed to work. The Ostrom guidelines are a nice take, from a different field, but they articulate something important about productive online communities. It’s interesting to think about whether these rules apply to recent online successes such as Foldit and GalaxyZoo.

Curtin-Hammett and Effective Molarity

This week’s Thursday Morning Problem Session involved a presentation by my graduate student, Soo, on some work published by Boons that concerned a stereoselective synthesis of 1,2-cis glycosides. The value of this chemistry is the bond forming event shown (in 2), guided by the attached chiral auxiliary:

The stereocentre in the appended group dictates the nature of the second ring, since the phenyl on the stereocentre goes equatorial. This therefore dictates the equatorial nature of the C-S bond. Because of all this, Soo suggested, the incoming nucleophile forms a bond that is axial stereoselectively. The chemistry behind the approach was originally described here.

At the end I questioned whether that’s a realistic explanation. Assume that the closure of that second ring by the intramolecular directing group is reversible, even to a very small degree (i.e. equilibrium between 1 and 2). Compound 1 will be much more reactive than compound 2 towards intermolecular attack by the hydroxyl (derived from the next sugar in the sequence). If we assume that the activation energy barriers of the attack of the intermolecular nucleophile are significantly larger than the barriers of the intramolecular reaction, then we can apply Curtin-Hammett and say that the form of the sugar that preferentially reacts with the incoming nucleophile is 1 (the more reactive of the two) no matter that it is the less prevalent form of the substrate. Naturally if that’s the case, then the oxacarbenium ion carbon that’s attacked is planar, ruining the argument about stereoselection. A possible way out is to say that immediately after formation of the oxacarbenium ion 1 from 2 (i.e. assuming it’s reversible), the local environment around the (soon-to-be) anomeric carbon is still influenced by the pendant chain (i.e. the molecule looks like 3), and that reaction is still therefore stereoselective. This argument is somewhat similar to the “ion pair” arguments that are invoked to explain nonracemic outcomes from apparently S_N1 reactions of enantiopure substrates.

Professor Crossley objected that the effective molarity (sometimes called “intramolecularity”) of the thioether was very high. What he’s referring to here is the extraordinarily high effective concentration of nucleophiles that are performing intramolecular cyclisations. Anslyn and Dougherty (Section 9.2) have some nice data on this, derived from Tony Kirby’s paper from 1980:

It’s intuitively obvious that constraining a nucleophile within the same molecule for a cyclisation can have dramatic effects on the rates of that cyclisation. So it is certainly true that the cyclised form 2 (rather than 1) is likely to be kinetically greatly favoured because of this. But if there is any oxacarbenium ion present, I think it will react rapidly and in preference to 2. Question is, is that ring closure reversible?

Daniel Koshland Community Park

We were out taking a walk through San Francisco and happened upon this park near Hayes Valley (Buchanan and Page). The name caught my eye – the Daniel E. Koshland Community Park. “Surely that’s not the same Dan Koshland who proposed induced fit for enzyme action?” I said to my wife. “What?” she said. So we took a picture:

Dan Koshland Community Park

I didn’t know that Dan Koshland was independently wealthy from family money derived from Levi’s jeans. It looks as though his father was Daniel Koshland Sr., formerly president of Levi Strauss and Co. I’m guessing this park originates from Dan Koshland Sr, rather than his biochemist son (but perhaps someone can put me right on that) since otherwise the park would have been in Berkeley. The HQ of Levi’s is in San Francisco near the Embarcadero, though they used to be on Valencia near the Mission (B), 4 or 5 blocks away from the park (A).

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Lexitropsins, Microgonotropens and House

I am writing a paper at the moment on some work my Honours student, Anthony Lo, carried out last year on an unusual distamycin mimic we synthesized. Distamycin A is a beautiful, crescent-shaped minor groove binder consisting of three amide-linked pyrroles and a couple of DNA-interacting groups on either end.

This molecule likes AT-rich regions of DNA, and the only thing more remarkable about its stunningly evolved fit is the sheer amount of wonderful science conducted to understand its mechanism of action and to develop variations in the basic structure so as to improve selectivity, or provide a predilection for GC bases, or fluoresce upon sequence binding. Dervan has been very active in developing a syntax for which components are needed to recognize a given sequence. The possibility of  “spelling out” a polyamide sequence recognizing any given DNA sequence has led to these molecules being called “lexitropsins,” presumably from “lex-” for “words” and “tropsin” for “turning”? Analogs containing alkylamines in place of alkyl groups of the lexitropsins are sometimes called “microgonotropens,” something I discovered from this review by Tom Bruice. Famous professors can start their biographies “Thomas C. Bruice dropped out of high school in the eleventh grade…”

I was digesting this vast and fascinating field when I was distracted by a House episode “Epic Fail”. The patient, a video games developer, is crowd-source-savvy and posts his symptoms online, rapidly receiving suggestions for tests and diagnoses in return. Part of the episode is the battle between the (small number of) highly trained doctors and the wisdom of the crowd. The patient even posts a reward, Innocentive-style. There are some interesting things here for anyone interested in open source, or open science. The plot alludes to the choice between following a well-trained expert or spending time sifting through many suggestions from the public. This is a recurrent objection that is raised about open source: “is it really worthwhile, given that one has to sift out junk?” and I am asked this on a fairly regular basis about our open chemistry project. The answer is complex and interesting and is the essential conflict between the Cathedral and the Bazaar. In the House episode the bazaar does rather well, with a caveat spoiler I won’t reveal.

Chiral Dice

Recent visitors to my office have been confronted with this on the white board:

How many stereoisomers of a die?

I want to clean it off, so I’m posting it here. It dates from a visit we had from Ben Davis last year as the Cornforth Lecturer. He was telling me that Ken Izumori from Kagawa has a collection (in, I think, wood) of all the possible stereoisomers of a die. This got me thinking about how many there are, and the picture’s the analysis. There’s probably a way of using this to cheat in a casino. Which would make one enantioenriched I guess.