Monthly Archives: March 2008

A burner by any other name…

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In case you didn’t know, today is National Bunsen Burner day.* Let the partying begin!!

A celebration of Bunsen’s contribution to the scientific lab does beg the question, though (with apologies to Shakespeare): Would a burner by any other name burn as hot? Would it be as useful for melting things in test tubes, or making spotters from pipettes? With more apologies to Bunsen, I’m going to venture a ‘yes’ on that one, but this could just be because my last Bunsen burner was not very useful (too sensitive to drafts), so I can’t imagine how things could get much worse.

On a somewhat related note, when I was in graduate school, we received word that the EPA would be coming through the lab to make sure we were obeying all the rules about proper handling and disposal of chemicals. While of course we were completely in compliance with these rules already, we wanted to be absolutely certain that we were following the EPA guidelines to the fullest extent, in particular in regards to the extent to which things needed to be named (or labeled) throughout the research space. As a result, we spent a fair amount of time labeling anything that had previously escaped our notice, such as chairs (‘Chair’), doors (‘Door’), walls (‘Wall’)… you get the idea. In the end, the EPA was very happy with us (and the chemistry department in general). Phew! Actually, the only group on campus that got any significant fines was the art department, who were happily throwing oil-based paint down the drain. Oops…

Anyway, back to the main idea: what are you going to do to celebrate such an exciting holiday? Adjust your Bunsen burner’s air vents? Sterilize/dry some flasks? Cook dinner by burner? Let me know if you think up any good ideas.

Catherine (associate editor, Nature Chemical Biology)

Spend a few minutes today to appreciate the value of this important scientific tool. We will let you determine how many minutes to spend in reflection.

It’s nice that I am allowed to determine my own actions. Thank you, holiday write-up person, for empowering me.

Reactions – Phil Gale

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1. What made you want to be a chemist?

It was the influence of three people. I went to Gateacre Comprehensive in Liverpool and had an excellent chemistry teacher called Dave Lutner. He was inspirational – I really enjoyed his classes. In those days, health and safety hadn’t taken over the world and we were treated to some fun demonstrations and had the chance to do a fair amount of practical work ourselves. Then, at university in the early 1990s I hadn’t found my niche until I started as an undergraduate student (doing a whole year of full time research) in Paul Beer’s group in Oxford. Paul is a supramolecular chemist and, at the time, was working on bis-crown ether molecules containing bipyridyl groups that could be used to control the conformation of the molecule via coordination to a transition metal. I found the idea that you could think of molecules as molecular machines absolutely fascinating and that was it – I was hooked! I did a PhD for Paul working on calixarene chemistry and then moved on to Jonathan Sessler’s group in Austin, Texas. I was very fortunate both to have the chance to work with Jonathan, who is an inspirational mentor, and to work on a project which resulted in the discovery of an important new class of anion receptor.

2. If you weren’t a chemist and could do any other job, what would it be – and why?

I’ve become increasingly interested in publishing and have had the opportunity to contribute to a number of journals on editorial boards and as editor. I’ve really enjoyed the experience and think it would be an interesting challenge to work full time in science publishing. With the potential rise of open access journals in chemistry and the general proliferation of journals I think the battle ahead will be to maintain quality. I think working towards that would be a really worthwhile goal.

3. How can chemists best contribute to the world at large?

I think chemists already make significant contributions to the world at large but these often go unrecognized by the public. We can fix this by engaging with groups outside the chemistry community – whether they be school children or politicians. We can’t complain that chemistry has a bad reputation amongst the public if we’re not prepared to put some effort into fixing the situation.

4. Which historical figure would you most like to have dinner with – and why?

Adolph von Baeyer – in the latter half of the 19th Century he started a lot of the chemistry that I’ve worked on over my career but without the aid of NMRs, crystal structures and HPLCs etc. I’d like to talk to him about his work and his mentor Kekulé.

5. When was the last time you did an experiment in the lab – and what was it?

If molecular modeling counts, then about three hours ago!

6. If exiled on a desert island, what one book and one CD would you take with you?

As a reminder of my youth, the CD would have to be New Order’s Substance. I’d need a large book for swatting mosquitoes on this island (I’m allergic to them) so I think I’d take the Lord of the Rings which has always been a favourite.

Phil Gale is in the School of Chemistry at the University of Southampton, UK, and works on supramolecular chemistry and particularly the binding, sensing and transport of anionic species.

Beating nature to save the planet

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It’s been a while since I blogged here – apologies. I haven’t been neglecting chemistry though – far from it. I’ve been ferreting away on a feature article, just out in Nature this week.

It’s all about trying to find ways to copy the processes in photosynthesis to split water and produce a fuel – hydrogen. Yes yes, I know it is already possible to split water, but the latests efforts have a longer-term goal of finding sustainable, friendly materials to do the job. And it is a lot harder than it might sound.

Nature uses catalysts to drive complex multielectron processes, but exactly what the molecular nature of these catalysts are isn’t known. So trying to directly copy them is challenging. And finding a completely different system that works as well, nay, better, is harder still.

A recent paper in Angewandte Chemie has a catalyst that can perform half the job, and impressive it is too, working as it does at room temperature and with reasonable turnovers. But still, it is a tetra ruthenium compound. Not likely to come in as an economic competitor to fossil fuels, unfortunately.

There will be a session at the ACS, organised by UCLA graduate students, called NanoPOWER that will likely address many of the challenges remaining for power, and fuel production. I’m hoping to be there to see what alternatives chemists can offer.

Journal journeys: Day 54, Housekeeping

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Sorry it’s been a while since the last JJ post – recruitment, portal and website issues have conspired to stop me from blogging about Nature Chemistry for a little while… but there are a few things I would like to mention:

1. Nature Chemistry is looking for another associate editor, to be based in Tokyo – here is an excerpt from the job ad:

As part of NPG’s expanding publishing programme in chemistry we are now seeking an additional Associate Editor, to be based in our Tokyo office, to work on Nature Chemistry and a number of publishing projects based in the Asia-Pacific region.

2. Nature Chemistry now has a Facebook page. I’m sure that half of the Sceptical Chymist readers have just groaned and the other half have let out some little whoop of joy (I’m just guessing at 50:50, for all I know it could be 99:1). Anyhow, consider it an experiment of some kind – let’s see where it goes… why not join and come along for the ride?

3. I will start the obligatory – “Is anyone in blogo-land going to the ACS meeting in New Orleans?” thread. I am, and a few other NPG-types are, and there’s always the possibility of a blogger get-together of some sort…

Stuart

Stuart Cantrill (Chief Editor, Nature Chemistry)

Reactions – Gary Siuzdak

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1. What made you want to be a chemist?

My career in mass spectrometry derived from its practical applications as it is such a diverse technology. This interest primarily comes from my enjoyment of mathematics, innovative physics technology and that mass spectrometry draws these things together allowing it to be applied to many areas of science.

2. If you weren’t a chemist and could do any other job, what would it be – and why?

A coastal surveyor in Alaska from May to August and a carpenter during the off months in Mulege, Baja.

3. How can chemists best contribute to the world at large?

Develop a room temperature, high current capacity, superconductor energy storage device.

4. Which historical figure would you most like to have dinner with – and why?

Luigi Amedeo, Duke of the Abruzzi (adventurer), with what, by our standards would be the crudest traveling means, he explored the world and his own physical existence. Or perhaps Samuel Johnson (English writer) for pure entertainment value.

5. When was the last time you did an experiment in the lab – and what was it?

1999, a set of metabolomics experiments designed, with a visiting high school student, on the effect of Krispy Kreme donuts on skin composition… the changes were very substantial and interesting. Among the many observations, we saw that in some individuals there was a dramatic increase in skin cholesterol almost immediately.

6. If exiled on a desert island, what one book and one CD would you take with you?

The Lesson (book) and the Squirrel Nut Zippers (CD).

Gary Siuzdak is at the Scripps Center for Mass Spectrometry, The Scripps Research Institute, California, and works on developing and applying new mass spectrometry technologies for metabolomics.

Chemiotics: The vanishing simplicity of chemical pathways in the cell

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Posted on behalf of Retread

So nat’ralists observe, a flea

Hath smaller fleas that on him prey,

And these have smaller fleas that bite ’em,

And so proceed ad infinitum.

– Jonathan Swift

Is anything like this going on in the cell? Consider mitogen activated protein kinase kinase kinase (abbreviated MAPKKK) — shades of Major Major Major in Catch-22. Recall that a kinase is an enzyme which attaches a phosphate group to (phosphorylates) one of the 3 amino acids with hydroxyls on their side chains — serine, threonine and tyrosine. A phosphate ester is formed in the process adding a significant amount of negative charge and some local bulk to the protein (and if the protein is an enzyme often significantly altering its activity).

And what is the target that MAPKKK phosphorylates? Why MAPKK, another kinase which itself phosphorylates MAPK (yet another kinase — I’m not making this up). MAPK phosphorylates a variety of proteins, among them transcription factors which turn on various genes.

All quite linear (sequential) and comprehensible. There is a nice chain of causality from the agent outside the cell (the mitogen) to the receptor for it, to MAPKKK and so on to a particular set of genes whose level of expression is altered with the net result being cellular proliferation (e.g., mitosis).

Discovering this pathway took a lot of hard work on the ras protein, which is mutated in 30% of all cancers. Just the steps from the mitogen binding to its receptor to ras and thence to MAPKKK are quite complex. It was a hard slog, one (linear) step at a time. But what if all this work was like the drunk looking under the street light for his key because that’s where the light was. Suppose far more than that is going on.

Instead of teasing out pathways one protein at a time, suppose you just threw a mitogen (in this case epidermal growth factor — EGF ) at a cell (OK, a cancer cell — the Hela cell — the workhorse of cancer research) and looked at every protein to see what was phosphorylated and what was not. Using advanced mass spectroscopy and some other cutting edge techniques [Cell vol. 127 pp. 635–648, 2006] did just that. Some 6,600 distinct phosphorylation sites on 2,244 different proteins were found. 924/6,600 sites showed more than a twofold change in the phosphorylated to unphosphorylated ratio.

In addition, the work was repeated at several time points within 30 minutes of EGF application, allowing the time course of phosphorylation at each site to be determined. The time courses of phosphorylation varied from site to site. Many proteins had more than one site phosphorylation. Even on the same protein the time course of phosphorylation depended on the site studied. At least 46 distinct regulators of gene transcription showed a greater than twofold variation in phosphorylation. It doesn’t take much imagination to see that adding a lot of negative charge would alter the ability of a transcription factor to approach DNA (which has one phosphate per nucleotide).

Where this leaves our notion of causality (which really is quite linear) and whether our minds are strong enough to comprehend these events is the subject of the next post.

Retread

I’ve got the whole issue in my hands…

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First things first: our April issue is now online. This is (as always, duh) a great one, including a comparison of cryogenic crystals conveying complex and coordinated connectivity in conduits, a synthetic sugar system to screen symptoms of severe sickness, and a pair of protocols to prepare and prove proper Phytophthora products.

We’ve also included a few photos from our recent symposium, and summarized some of our thoughts from and experiences at the meeting in our editorial this month.

On the topic of scientific gatherings, I thought it might be interesting to hear from you all about conferences you look forward to. For example, in contrast to my recent question about conferences that are a bit scary, what are your favorite conferences, and why? Is it all about the content, or have different ways of getting your daily recommended allowance of science made a big impression on you? What would you most like to do at a conference, if you could plan one yourself? We’re in the midst of planning our next symposium, so we’d love to hear any fun ideas you’ve got tucked away…

Catherine (associate editor, Nature Chemical Biology)

Reactions – Tom Welton

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1. What made you want to be a chemist?

I only took A-level chemistry because it completed a sensible set of three. Then, the first thing that we learned about was atomic structure. I can remember thinking that this was the most interesting thing that I had ever heard. From then on, I was hooked.

2. If you weren’t a chemist and could do any other job, what would it be – and why?

I had always thought that I would be an aeronautical engineer. I had always loved aeroplanes.

3. How can chemists best contribute to the world at large?

Aside from the obvious contributions in terms of the products of the chemicals industries and understanding how the world works, I think that most chemists are well grounded, practical people who like to proceed on the basis of evidence. These qualities seem to be surprisingly rare in today’s world. Keeping these in the public discourse is really important.

4. Which historical figure would you most like to have dinner with – and why?

This is the question that I have found the most difficult to answer. Do you go for someone who has had huge impact on the world, a person of great beauty or famous charm or a damn good comedian? I don’t know.

5. When was the last time you did an experiment in the lab – and what was it?

If you mean to have finished an experiment, it’s so long in the past that I can’t remember. I can remember very clearly when my two most experienced PhD students came to my office one day to speak to me on behalf of the group. They told me that whenever I came into the lab to do some practical work, I left things half completed and that they had no idea of what to do with the mess that I left behind and that I was slowing their progress. So, I stopped.

6. If exiled on a desert island, what one book and one CD would you take with you?

The CD is easy, it would be the complete collection of Round the Horne. I’ve always quite fancied reading the Mahabharata – at least it’s good and long.

Tom Welton is in the Department of Chemistry at Imperial College London and works on the effects of solvent-solute interactions on chemical reactivity, particularly in room-temperature ionic liquids.

Materials Girl: Then and now

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Posted on behalf of Materials Girl

Freshman year passed in [what is now] a blur. I mostly recall slaving over o-chem labs, studying relentlessly, and pondering a major in chemistry. Adaptation to university life was immediate and painless, apart from coping with the much heightened level of academics.

For instance, semi-brainless writing was an A+ in community college (during high school), while just scratching an A- at the university level. It went from simply using proper grammar and sounding vaguely intelligent, to really having to analyze and think things through to create new ideas. Science and math also seem to follow that route – going from primarily plug & chug on multiple-hour exams to 50 minutes of where-the-hell-did-this-come-from?!

So, returning from the tangent of academic discrepancies, I struggled during the first year of university, but never despaired for longer than a day. If anything, it was always o-chem causing stress…

Speaking of which, upper-division lab begins next quarter and I haven’t dealt with o-chem for over two years – it’s all been inorganic and physical since freshman year. My labwork has barely involved chemicals or spectroscopy, and even less of hot plates, TLC, separatory funnels*, etc… In essence, my doom is waiting around the corner and I’ll be re-studying like a madwoman. What do you consider the main tenets of o-chem book-knowledge and laboratory technique? What should I focus on?

*Granted, after hearing a good number of professors recount horror stories on the misuse of sep funnels, it’s hard to forget, say, shaking one without holding it closed. Still, it sounds terribly amusing to see someone else’s reaction propel a stopper across the room…

Chemiotics: The decline of the master gland and the rise of feedback

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Posted on behalf of Retread

Endocrinology was pretty simple in med school back in the 60s. All the target endocrine glands (ovary, adrenal, thyroid, etc.) were controlled by the pituitary; a gland about the size of a marble sitting an inch or so directly behind the bridge of your nose. The pituitary released a variety of hormones into the blood (one or more for each target gland) telling the target glands to secrete, and secrete they did. The master gland ruled.

Things became a bit more complicated when it was found that a small (4 grams or so out of 1500) part of the brain called the hypothalamus sitting just above the pituitary was really in control, telling the pituitary what and when to secrete. Subsequently it was found that the hormones secreted by the target glands (ovary, etc.) were getting into the hypothalamus and altering its effects on the pituitary. Estrogen is one example. Any notion of simple control vanished into an ambiguous miasma of setpoints, influences and equilibria. Goodbye linearity and simple notions of causation.

As soon as feedback (or simultaneous influence) enters the picture it becomes like the three body problem in physics, where 3 objects influence each other’s motion at the same time by the gravitational force. As John Gribbin (former science writer at Nature and now prolific author) said in his book ‘Deep Simplicity’, “It’s important to appreciate, though, that the lack of solutions to the three-body problem is not caused by our human deficiencies as mathematicians; it is built into the laws of mathematics.” The physics problem is actually much easier than endocrinology, because we know the exact strength and form of the gravitational force.

Organic chemists dearly love linearity. Nothing is more linear and causal than a multistep synthesis. We always search for conditions producing just what we want in high yield with as few unwanted products as possible, thank you. Le Chatelier’s principle is used again and again to force reactions to go just the way we want. It is a type of thinking that will not help us understand what is going on within our cells.

At one time it was thought that we had about 100,000 genes coding for proteins. The best current estimates are around 20,000. These genes code for structural proteins (like those of muscle and bone) and enzymes which do things like metabolize sugar or build the components of structural proteins (amino acids) or of DNA and RNA (nucleotides). We are gradually finding out that a lot of our genes function as controlling elements.

For instance, we have 478 genes for enzymes called kinases which form phosphate esters on the hydroxyls of threonine, serine and tyrosine of proteins, radically altering their function usually (the phosphate group adds a lot of negative charge). We have 107 genes for enzymes (called phosphatases) just for removing the phosphate from tyrosine (never mind serine and threonine). Another 600 or so genes code for enzymes which add (or remove) a small protein called ubiquitin from other proteins. Again feedback, control and nonlinearity.

Where this leaves the notion of causality in the cell, and worse, our ability to comprehend it — we do think linearly after all — will be the subject of the next post.

Retread