Authors - alphabetical vs. by contribution

After my first post on Authors and who goes on papers I have received quite a few emails from people and had some interesting discussions with some of my colleagues. It seems that everyone has a good story on this topic. Something that I've noticed can give rise to some heated discussions is whether authors should be listed alphabetically or according to how much they have contributed, i.e. the first author did most. From what I've gathered so far the alphabetical system seems to be a chemistry thing. When I mention this concept to people in biology/biochemistry they are outraged. In their area you really need to be the first or second author for the paper to carry any serious weight on your publication list. After thinking a bit about all this I have reached two conclusions that may or may not be right:

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(1) The alphabetical system only benefits the supervisor. The supervisor no longer has to have any troublesome discussions about who did what.

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(2) The contribution system also benefits the people that actually did the work. In many academic institutions and companies they look for first authorship's on papers. This is the only way they can determine if people did any meaningful science. From third author and down they could have ended up on the paper for close to nothing.

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And then there are the supervisors that mix things up:

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(1) Many supervisors will always put themselves last and everyone else by alphabet?

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(2) Others will always put themselves first and everyone else alphabetical (or by contribution). I suspect they do this so that the paper will be referred to as "supervisors name" et al. rather than "students name" et al.

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I have been through two alphabetical places and four by contribution places and I have reached the conclusion that if you want your name at pole position (at the alphabetical places) you just have to do all the work yourself. And finally just in case anyone thinks that I'm moaning and I'm unhappy about how things have panned out for me - I'm not - I just thought the topic was interesting. D!

NMR tube cleaner

I have a lot of NMR tubes and as a result I don't clean them very often and when I eventually decide to do something about it I'm faced with something like 30 dirty tubes. Now firstly if you work this way you have to soak the NMR tubes as soon as you are done with them. If you just let them evaporate to dryness you are in trouble. I normally just empty the tube and fill it to the lip with acetone and cap it. This way it wont dry out for months.

When I was cleaning my tubes the other day I had three synthetic organic chemists from three different countries walk up to me and ask what I was doing. This was somewhat surprising so I've decided to share with you what I thought was common knowledge: The NMR Tube Cleaner. These things are commercially available (expensive) or you can have your glass blower make one at a reasonable price. You can see my set up on the picture above. This is how it works:

(1) take the cap of your NMR tube and attach it to its base

(2) stick the tube in the cleaner (see picture) so that the cap seals the opening at the top

(3) squirt solvent(s) into the solvent opening (see picture).

The system is under vacuum and the solvent gets sucked through a thin tube that goes to the bottom of the NMR tube. It is very effective and I usually do a combination of solvents to get rid of everything. Its smart to have a three way tap between the cleaner and the pump so that you can let air into the cleaner without having to turn the vacuum off all the time. There's an NMR tube entry at Wikipedia that also describes the NMR tube cleaner. D!

Authors - who goes on the paper and why?

Yes I know! It's pretty quiet around here. My Internet connection at home is dead. I'm on the phone with my Internet provider every day to resolve this issue but it is a slow process.....So I guess a bit of blogging from work is required (Sorry boss. I'll run that column in 15 minutes). I'm writing papers at the moment and this always brings up the issue of authors. Who's on and who's off? Over the years I've experienced some pretty disturbing things in this category:

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(1) You send the paper off to your boss for proof reading etc. and it comes back with another name on the paper! Why? The boss feels bad about not giving that person credit for something completely unrelated and is trying to make up for it.

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(2) People doing routine analysis go on all papers. This category is a bit of a grey area as some techniques may be routine to the person doing it but does require years and years of experience. An interesting issue in this category is X-ray crystallography. Many older scientists (50+ years) don't realise that this has become a routine operation and religiously put the x-ray dude on all papers. Granted in the world of small molecule X-rays the crystallographer should go on sometimes when things aren't trivial. However, 90% of the time this is definitely not the case.

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(3) Everyone in the lab goes on all papers! This is really far out but nevertheless the policy in some labs. By everyone I also mean the technician making up the solutions.

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(4) And then there are the totally reasonable, serious scientist that will actually ask to have their name removed from the paper as they don't think they have contributed enough. I like this person much more than the evil pseudo-scientist snake that will do anything to sneak their name on a paper.

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There's much more where this is coming from. Another post on the topic coming up shortly. D!

Pay Rise Cake

Regardless of whether you are working in industry or academia there will be occasions where you will have to supply cake (If this isn't the case you've got it all wrong and should bring some cake to work tomorrow). Now I will concede that there are decent commercially available cakes that I will eat with great pleasure. However, if you consider yourself a synthetic chemist, be it organic or inorganic you MUST make the cake yourself. It's way easier than synthetic work and the final product doesn't require chromatography, tastes great, won't kill you and will make people happy. So here's a recipe to help you guys out if you have no idea what to bake. It's the cake that a friend of mine has named the pay rise cake as you are guaranteed to impress your boss with it. It's a fairly expensive cake to produce but believe me its worth it.

Banana and Chocolate Cake aka Pay Rise Cake [Serves many, 20+]
Ingredients
Flour (500 g)
Sugar (500 g)
Quick oats (50 g)
Butter (300 g)
5 x 50 g eggs
8 ripe bananas (ca 700-800 g when peeled)
Skim milk (150 ml)
Vanilla sugar (5 tsp)
Baking powder (5 tsp)
Salt (3 tsp)
Dark chocolate (300 g, Don't be a cheap skate and use good stuff. For example Lindt 70%)

Procedure
(1) Melt the butter - do not reflux
(2) Beat the sugar with the melted butter
(3) Add the eggs (not the shells) and beat
(4) Add milk and bananas (mash the bananas first) and beat
(5) Add flour, quick oats, vanilla sugar, baking powder and salt and beat
(6) Chop some of the chocolate (200 g) and mix it with the dough (don't beat it at this stage)
(7) Transfer the dough to a large baking tray (eg. 30 x 30 x 5 cm) and bake in the centre of the oven at 180 oC for 40-45 minutes. When the dough doesn't stick to a metal object it is finished (you basically insert a metal object such as a knife into the cake and check if anything is sticking to the knife). It is a good idea to check on the cake after 30 minutes as ovens vary greatly in performance. The cake approximately doubles in size depending on the baking powder used.
(8) When the cake has cooled to room temperature cover it with a thin layer of melted chocolate. You have to be careful when melting the chocolate. First chop it up (100 g) then put it in a suitable container (eg beaker) and melt it using a hot water bath whilst stirring. Do NOT add water, milk or anything else. Simply use good quality dark chocolate with a high cocoa content and you are in business.

Enjoy the cake - it is really nice. The cake is excellent for freezing and I generally have some tucked away at -20 oC for "emergencies". If a pay rise isn't enough and you are going for a promotion then you may consider serving it with some fresh strawberries. D!

Retraction - Azepinoazepine or Viologen?

I believe a new post is way overdue. Since my last post I almost ended up becoming a regular writer for a chemistry magazine and I have been reading an excellent book: Organic Synthesis - Strategy and Control. In due course I'll post a review of this most excellent book. Anyway, let's get to the point. Additions and corrections to papers are quite common in organic chemistry but you don't see retractions very often. Well it appears that Yamaguchi, Tsutsui and Sato where getting a little bit too excited about their synthesis of azepinoazepines (1). However, after the paper was accepted in Angewandte Chemie someone (probably Thomas Vaid, Washington University, US) was kind enough to point out that they had in fact made some viologens (2) (See Vaid's paper on viologens here). I guess that paper didn't last long on the CV. In Yamaguchi's defence I will say that it isn't entirely trivial to sort out the 13C NMR spectra of these compounds and when you are actually trying to make something specific you have a tendency to get carried away at times. I just hope this sort of thing never happens to me. On a similar note someone I know recently had a rather controversial opinion paper accepted in a high impact journal. However, whilst making changes suggested by the referees she came to the realisation that they couldn't actually draw the conclusions they had been making in the first place......I guess that's better than having to retract it later on but it's gotta hurt. D!

Behold cyclohexane!

Recently I was flipping through a magazine published by a learned society and my eyes were caught by this rather interesting picture. The aim of this photo is to encourage scientist to publish in certain society journals. Firstly, it seems rather lame that the teachers is pointing at cyclohexane that appears to be in its perfectly flat conformation? Is that the most acidic proton he's pointing at? Secondly, what is going on with the students. I have a feeling the guy to the left is a werewolf. Or maybe he's just split up with the girl to the far right which would explain why she looks like she's about to commit murder. And what's going on with the woman in the background? It's cyclohexane people and not Brevetoxin so stop looking at it like that. D!

Septanosides

We hardly finished talking about oxepans and Ferrier rearrangements when I spotted a paper on the synthesis of septanosides by a very similar route. This time the nucleophile is sodium methoxide and the rearrangement proceeds in an impressive yield to give a single anomer!

Interesting work by Ganesh and Jayaraman at the Indian Institute of Science in Bangalore. D!

Oxepane Nucleic Acids - Part II

Before I get started let me say that I think this is a good paper by Damha and that the compounds are genuinly interesting. However, I did find a number of things I believe could be improved.
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In the preivious post I gave the Tm data for homo-adenine and homo-thymine Oxepane Nucelic Acids (ONA) and it was quite clear that the low melting temperatures renders ONA useless from a pharmaceutical point of view. However, as I said it has a high stability in serum and activates RNase H. To date only very few oligonucleotide analogues have activated RNase H. The authors seem to be of the opinion that only four RNase H activating oligonucleotide (ON) analogues have been reported to date. However, they seem to forget the very first and most famous analogue - Phosphorus monothioates (PS). PS have been well known since the early 80s and ISIS Pharmaceuticals tried deveoloping drugs based on this class of analogues for a loooong time (they may still be doing so for all that I know). Anyway, let's have a look at the chemistry. They choose a somewhat surprising starting material and do a very funky Vorbrüggen coupling. I've never seen anything quite like it (notice the counterintuitive stereochemical outcome). Very impressive although the yields are poor. They get a fair bit of the diene oxepan product and some of the alfa-anomer too. Nevertheless a nice piece of work. Apparently an adaption of some work by Hoberg (JOC, 1997, 62, p. 6615) that I haven't checked out. People who haven't worked with nucleosides probably don't realise how difficult even the simplest transformations can be a times. Thymine and Adenine are by far the two "easiest" nucleobases to deal with. Cytosin is bad news and Guanine can be an outright nightmare. This is probably the main reason why everyone tests T and A first. Anyway, after taking the protection group off they proceed to hydrogenate the olefin which goes well. However, from here on it's a bit nasty. Firstly, they decide to use monomethoxy trityl (MMT) rather than dimethoxy trityl (DMT) because they get better yields this way. Now different molecules behave differently but I have a hard time accepting that you can't get DMT on in a higher yield than they report for MMT protection. Very odd! I wish they informed what happens instead. Maybe di-protection is a problem for some reason? Furthermore, they proceed to synthesise the phosphoramidite using the classic phosphoramidochlorodite (PCl) reagent. I see this all the time. Virtually, everyone in the area is using this phosphitylation reagent instead of the superior phosphordiamidite (PN2) reagent (See below). Back in the Jurassic when I used to make phosphoramidites I always used PN2. As a consequence no chromatography was necessary and I got >95% yield. We published a paper on how to make LNA (pioneered by Wengel) phosphoramidites using this reagent some years ago (Synthesis, 2002, 6, p. 802). Anyone interested in improving their phosphoramidite synthesis can request a copy (curlyarrow@gmail.com). So later on they proceed to synthesise their oligonucleotides and only achieve coupling efficiencies of 98-99%. As always it is hard to know why the yield is reduced. I wonder if the use of MMT protection has anything to do with it. One final comment regarding their conclusion. They seem to spot a connection between RNase H activity of ON analogues and sugar conformer flexibility along the ON strand. However, they have just mentioned that alpha-L-LNA is a known ON analogue that activates RNase H. This analogue contains a highly constrained bicyclic sugar (See Figure) and hence doesn't support their conclusion. They could conceivably be right. Maybe some other mechanisms are at work with alpha-L-LNA but I think they should at least have mentioned this. Anyway, overall a good paper from this Canadian research group. Keep them coming. D!

Oxepane Nucleic Acids - Part I

The chemistry you start your career working with tends to stick to you. Stuff you work on later seems much easier to shake off. Anyway, I started as a nucleoside/oligonucleotide chemists and although what I do now is miles away from this area every time my eyes wander over a graphical abstract with a nucleoside I stop. I just can't help it. It happened again the other day. Oxepan Nucleic Acids (ONA). Can you believe that it hasn't been made before. Apparently, no one has gone beyond the six membered ring until now. Now ONA is not a great nucleoside analogue. The T15 and A15 ONA oligonucleotides (ON) have affinities less than 5 oC towards DNA, a very low affinity towards itself (ONA T15 + ONA A15 = 12 oC) and a similar Tm towards RNA. In other words ONA is not suitable for antisense purposes due to the very low Tm. However, ONA is very stable towards nucleases and importantly activates RNase H. Now before I continue I should explain what Tm, antisense and RNase H is to the uninitiated. Firstly, Tm is the temperature at which 50 % of a duplex has denatured, ie. high Tm = stable duplex. Secondly, antisense is a different approach to drug development targeting RNA rather than proteins. The idea is to knock the RNA out before it gets translated into protein (See figure). This is achieved by synthesising an antisense ON that is complementary to your RNA target. The mechanism of action for antisense is either:
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(a) Inhibit the translation to protein by physically blocking the RNA strand making it impossible for ribosomes to translate it
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(b) Activate the enzyme RNase H that specifically targets DNA-RNA duplexes and only degrades the RNA strand.
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A lot of people in the field believe that antisense can only work effectively with RNase H activation and I tend to agree. The cell is amazingly efficient at making RNA and translating it to protein so if you have to get stoichiometric amounts of antisense ON to RNA into the cell you are likely to have a problem. The beauty with RNase H activation is that the system is catalytic. In other words the antisense ON gets released after RNA degradation and moves on to the next victim. The problem is that you cannot use regular DNA for antisense purposes as it has a very short half life in serum (~15 minutes). So you have to devise an analogue that is stable in serum, has high affinity towards RNA and activates RNase H. Now obviously this is no easy feat so why bother? The (theoretical) advantages when compared to traditional protein targeting drugs are:
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(a) Complete selectivity only for the intended target
(b) You can target anything involving RNA
(c) The chemistry is the same every time. You just have to figure out what the sequence of your target is and synthesise the required ON
(d) Getting drugs to market is rapid because drug development is significantly faster
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Obviously, things are much more complicated than this. Antisense was the big thing in the 80s. It was going to cure everything within the next decade but the reality is that only one product has made it to market. It's an ON called Vitravene (ISIS Pharmaceuticals) that prevents AIDS patients from going blind by targeting cytomegalovirus retinitis. That said a lot of advances have been made and there are numerous antisense ON in late stage clinical trials. Anyway, after this super condensed course in antisense ON I think we are ready for the actual paper. I'll let you off the hook for now. The next post should be up in a couple of days. D!

Still breathing

I happened to look at Curly Arrow the other day...it's now been over a month since my last post! Not good, not good at all. Taitauwai even enquired about my well being. Well I'm still alive (sort of). My brain is slightly fried. I'm trying very hard to get some papers written whilst also attempting to set a new lab up, get my new projects going and phase new group members in and make their projects take off....yes I'm fairly busy. All my blogging time has effectively become paper writing time. Anyway, I have lots of things I would like to share at Curly Arrow and I'll try real hard to get some stuff posted. Whilst getting new gear for the lab I stumbled over an old box containing a virtually unused Vibro-Mischer - Das ideale rührwerk für Labor und Betrieb. Check out this nice poster I found in the box. That is one sexy model they picked to promote their products. If you click on the image you will get an enlarged version. D!