The Sceptical Chymist

1. What made you want to be a chemist?

Science ran in my family – my father was a geology professor and my mother was a botanist. I used to visit my father at work and the geology department had display cases with beautiful crystalline minerals that used to fascinate me. The breakthrough came when I first encountered chemistry at school and found that I didn’t have to be limited to gazing at beautiful crystals in a glass case, I could make them myself!

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

I would be drawn to something that had a similar combination of being people-oriented, practically-oriented and involving lots of problem solving. After I was drawn into chemistry with its necessary hours of time spent in labs I became very interested in outdoor activities – not always a good mix. I have also always liked writing and reading and been interested in the publishing industry. How could I combine all of these? Maybe I should have been born 150 years ago and been one of those intrepid explorers that broke new scientific ground by travelling to exotic places and observing and documenting what they found there.

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

The solutions to the major problems facing the world at present – finding energy sources that can provide quality of life for the world’s population without further damage to the environment – will be chemical solutions. Particularly in the area of energy and sustainability it is chemists who are defining the problems and seeking the answers.

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

Alfred Stock. I teach and research in boron chemistry and it amazes me how Stock managed to achieve such a wealth of chemistry, preparing and handling toxic and air-sensitive compounds without the benefit of our present-day sophisticated equipment and analytical tools.

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

It depends on what counts – yesterday I helped an undergraduate student in the teaching lab crystallise her nickel complex. The last time I did a real experiment in the lab would have been in 1993 on sabbatical leave with Phil Power at UC Davis.

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

The book would be the Bible – good ripping yarns, narrative history, lots of pages with fine print so it would be a lengthy read, and maybe have some handy advice for coping with the spiritual and psychological side of being exiled on a desert island. The CD would be Handel’s Messiah – similar reasons, music that goes from the depths of despair to the heights of joy, plus I could sing along to the alto part.

Penny Brothers is in the Department of Chemistry at the University of Auckland, New Zealand, and works on porphyrin and corrole complexes containing two boron atoms, which show unusual structural and reactivity at both boron and the ligands.

Posted by Alison Stoddart at 05:24 AM | Permalink | Comments (0) | TrackBacks (0)

Morning everyone, here are this week's research highlights:

Viscosity is a property that's easy to think about on the bulk scale (pouring syrup compared to water, for example), but it's less easy to get your head around it on a molecular scale. But using a molecular rotor, viscosity can be measured within cells...

Heard of the Eshelby twist? No, it's not a 1950s dance craze, but a type of crystal defect, and it can be exploited to make some very pretty looking nanotrees...

And finally this week, a subject quite dear to my heart: solid-state synthesis. Having spent rather a long and frustating time during my PhD trying (and failing) to make a whole raft of compounds that calculations predicted should exist, I'm glad to see that other people have been successful in making a new polymorph of lithium bromide — exactly as predicted.

Enjoy.

Neil

Neil Withers (Associate Editor, Nature Chemistry)

Posted by Neil Withers at 04:51 AM | Permalink | Comments (0) | TrackBacks (0)

Posted on behalf of Retread

Reading the biomedical literature is like reading a large Russian novel with thousands of characters who interact in unexpected ways. A recent paper [Nature Medicine vol. 14 pp. 382 -391 (2008)] brings together 3 such actors — CFTR, the protein mutated in cystic fibrosis, ceramide, a molecule only of interest to neurologists until recently, and amitriptyline, a drug for depression whose mechanism of action was (seemingly) known.

Let’s start with CFTR, a huge protein (1480 amino acids). CFTR mutations cause cystic fibrosis, the commonest hereditary disease of Caucasians. There must be some selective advantage to CFTR mutations as over 600 were known as of 2003. However just one accounts for >50% of all cases. It is a deletion of phenylalanine at position #508 (showing just how delicate protein structure and function really is). One guess is that the mutants protect against intestinal pathogens (infantile diarrhea kills many children in the developing world).

Ceramide and its derivatives contain two saturated unbranched hydrocarbon chains (16–20 carbons long). They are found in myelin (the wrapping of nerve fibers) which is mostly lipid. All sorts of awful hereditary neurological diseases (usually affecting children, but fortunately rare) are caused by the accumulation of molecules containing ceramide. In recent years, ceramide's effects on non-neuronal cell proliferation and/or cell death have become prominent. Ceramide is a second messenger. The intracellular effects of ceramide in the normal workings of the brain haven't been much studied.

Amitriptyline (Elavil) was one of the earliest antidepressants. We all knew how it worked; by blocking the re-uptake of neurotransmitters such as serotonin and norepinephrine from the synapse (except that this is an acute effect and this class of drugs — the tricyclic antidepressants — takes a few weeks to work).

Surely you see how all this fits together at this point. No? I didn't either. Read on...

It turns out that CFTR mutations increase the levels of ceramide inside the lungs (the primary site of infection in cystic fibrosis). This is caused by alkalinization of the intracellular sites where ceramide is broken down. Elevated ceramide levels are thought to increase cell death, resulting in lung infection (the bacteria have more to munch on).

Where does amitriptyline fit in? It lowers lung ceramide levels. How? By decreasing the amount and/or the activity of an enzyme (acid sphingomyelinase) which breaks down a precursor of ceramide. The paper is silent on the mechanism(s) by which this happens (but does give two references #24, #25). Treating transgenic mice with mutant CFTR with amitriptyline decreases the frequency and severity of their lung infections. Amazing.

Where does the effect of amitriptyline on neurotransmitter re-uptake fit into all of this? It doesn't, and that's just the point.

Nowadays, medicinal chemists design organic molecules to fit into slots of proteins whose function they are trying to alter. The tricyclic antidepressants weren't discovered this way (they are much older), but papers like Mol. Pharmacol. vol. 50 pp. 957–965 (1996) found crucial amino acids in the re-uptake protein to which they bound. A fairly open and shut case for their mechanism of action.

Except it isn't. Who knows how many designer drugs are really working the way we think they do. A cautionary tale indeed...

Posted by Stuart Cantrill at 10:11 AM | Permalink | Comments (2) | TrackBacks (0)

Posted on behalf of Materials Girl

It is my theory that organizations should raffle off spectrometers instead of, say, iPods. For example, various boxes of kimwipes have been advertising trips to Jamaica and home theater systems. While anyone could use a vacation, maybe we’d be stuck in lab less often if not for the long line to obtain an NMR spectrum…

Speaking of which, o-chem lab is going splendidly – apart from a handful of volatile lachrymators and an overcrowded class. I’d forgotten how semi-exhilarating it is to soak for half a day in the fumes of acetone and whatever concoctions are being nuked by the students. As suggested by Sarah, I got my hands on “Organic Chemistry as a Second Language”, but fortunately haven’t needed to use the books for more than a reference. I mostly just have to memorize peaks and trends for the exams. psi*psi was quite right: "Studying doesn't help for labs – you have to be able to think on your feet, since the unexpected can and does happen."

So here’s a question. In a week’s experiment, only one student obtains the desired powder (instead of an oil), but the NMRs come out messy after the higher-ups fail to mention that the product is hygroscopic and shouldn’t be dried in air. Who did a better job?

Posted by Stuart Cantrill at 08:31 AM | Permalink | Comments (2) | TrackBacks (0)

Posted on behalf of the Prospective Professor

After months and months of grueling travel, crazy cab drivers, late night practice talks and waking up wondering what city I was in, I thought the worst of it was over. Little did I know that the fun had just begun. I am happy to say that I was able to find a job, and not just any job, but what seems to be the “perfect” fit for me. But after a few weeks of celebration and relaxation, that little voice started up again, “what have you gotten yourself into?!” I’m about to start a job for which I have never been trained!

Certainly my feelings aren’t unique. I’ve had conversations with countless people over the years discussing this very issue. Most of us will have spent at least 7 years pursuing our doctoral degree and doing postdoctoral research. And during this time, we may teach a few lab sections, write a quiz or two and hopefully compose a fellowship application. But never during this time do most of us get training in lab managements skills, mentoring techniques or budgeting (time or money). In essence, every step of my training has prepared me to be a bench scientist. And lets face it, after so many years of schooling I’m lucky if I can budget my monthly groceries let alone supplies for an entire lab, as well as funds to make sure my students can hardly afford their groceries!

Everyone tells me that I will learn with time. I just hate to think of the disasters that will happen in the meantime: Exams with an average score of 17%, a student crying after groups meeting or a lab left empty on the weekends (horror of horrors!). I will start my new position filled with nervous excitement and ready to learn many new lessons. The first question on my mind is, how do I attract students to my lab? I keep having flashbacks to junior high dances where we all waited at the side of the gym desperately hoping that someone would ask us to dance and wondering, “will anybody like me??”

Posted by Catherine Goodman at 02:52 PM | Permalink | Comments (2) | TrackBacks (0)

1. What made you want to be a chemist?

When I was a junior high school student, I was charmed by the periodic table. I have never lost interest in it because of its beauty. I needed to understand the nature of all atoms. Now, there is a big Japanese poster of "A periodic table for a family" produced by the Japan Foundation of Public Communication on Science and Technology in my office, so I can always see it.

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

A painter or a farmer. One of my grandfathers was a painter. He painted beautiful pictures of plants or animals on Japanese traditional cloth. My other grandfather was a rice farmer. He grew Koshihikari, the very popular and most expensive variety of rice in Japan. My family considered me to be the most likely successor in either event.

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

Education. People tend to keep chemistry at a distance. A product that originates from natural resources is highly thought of by people, in other words, they tend to be afraid of "a chemically synthesized compound". For example, vanilline extracted from vanilla beans and chemically synthesized vanilline are virtually the same compound, but they will choose the former even if it’s three hundred times more expensive than the synthetic one. It's crazy! I think the goal of chemists is to produce people who have high scientific or chemical literacy by using our chemical knowledge.

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

Prof. Adolf Butenandt, Nobel Prize winner, and also the person to discover the first insect pheromone, bombykol. I am interested in bio-regulators such as insect or microbe pheromones and hormones. I would like to hear his private lecture about his historical work on the isolation of bombykol.

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

Yesterday. I am active in our lab. My teacher and master, Professor Kenji Mori (now 73 years old), is still active in his lab! So I can't retire.

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

I like movies, especially Science Fiction movies. So, I would take the soundtrack of Star Wars and explore the island with the music in the background during the day. And I will go on reading Crime and Punishment by Fyodor Dostoevsky at night.

Arata Yajima is in the Department of Fermentation Science at the Tokyo University of Agriculture and works on the synthesis of natural products and biosynthetic intermediates interest at the interface of chemistry with biology particularly the microbe pheromones and rice phytoalexins.

Posted by Alison Stoddart at 05:22 AM | Permalink | Comments (1) | TrackBacks (0)

Another Friday, another batch of Research Highlights for you all to enjoy.

Steve's is about a pretty clever hydrogel. Hydrogels are potential carriers for drugs, but how do you get them to release their cargo in the right place? Aptamers are the answer...

Gav has written about some work by Richard Zare's group that looks at how viruses might 'break in' to cells. They used surface plasmon resonance to study a model virus attaching itself to a model cell.

And finally...oligoamide foldamers are strings of amides or amino acids that...well, fold up. A bit like proteins or DNA do. But if you can get them to fold AROUND something, you can use them to trap molecules. Jane tells us more about work done to this end in France and China.

Hope you enjoy this crop - if you have any feedback or comments, please let us know!

Neil

Neil Withers (Associate Editor, Nature Chemistry)

Posted by Neil Withers at 04:42 AM | Permalink | Comments (0) | TrackBacks (0)

Hi everyone,

This week the Nature Chemistry team have been thinking about how we display our wonderful papers (when we finally open the doors and eventually publish a paper, anyway).

We’d really like to see what everyone else thinks about some of the things we discussed after looking at what other journals have to offer.

So, the things we’re interested in:

(1) HTML vs PDF: does anyone read the HTML articles? Do you read the PDF on-screen or print it out?

(2) Big vs little graphics: what does everyone else think about the tiny size of the graphics in ACS html articles?

(3) Tagging/’semantic web’: what do you think about the toys on the RSC’s Project Prospect? What kind of things would you like to see tagged/linked to other content in Nature Chemistry? For instance, Steve would love to do something with named reactions.

(4) 3D molecular structures: do these help your understanding of a paper?

(5) How useful to you are InChIs and SMILES?

(6) Forward linking: the RSC and Elsevier/Science Direct offer this – do you use it? Would you use an RSS feed that alerted you to new citations of a particular paper.

(7) Would you actually comment on papers if there was a comments box at the end?

(8) We really like the Biochemical Society’s HTML article style (sample one here) – do you?

If we could get a deluge of posts about this one, we’d be overjoyed! And this is your chance to voice your opinion on what a Nature Chemistry paper should look like.

Neil

Neil Withers (Associate Editor, Nature Chemistry)

Posted by Neil Withers at 06:13 AM | Permalink | Comments (17) | TrackBacks (0)

Posted on behalf of Retread

Back in the 80s when artificial intelligence (AI) was going to make humans obsolete, LISP was the programming language of choice for AI. As a neurologist I was interested in intelligence in any form (machine or otherwise) so I tried to learn it. Most programs looked like gibberish. There was a great quote in a book "Let's Talk LISP" after a particularly convoluted piece of code — "Relax you, never understand anything, you just get used to it".

I think the same thing has happened with our understanding of biologically relevant proteins. We've just become used to the fact that biological proteins have a dominant shape. However, we also know that other polymers don't. DNA and RNA certainly don't have a single shape.

So why do biologically meaningful proteins have one? Consider enzymes. The amino acid side chains comprising the active site are found all over the protein rather than next to each other in the sequence. Chymotrypsin, one of the best studied enzymes, has a catalytic triad made from histidine #57, aspartic acid #102 and serine #195. To function, they must be brought near to each other and held there fixed (and in the proper orientation to boot). The same holds for structural proteins that make up muscle and the cytoskeleton.

Yet only 10 kcal/mole — 2 hydrogen bonds — is enough to denature them. Not much of an activation energy — not even close to a covalent bond. Once denatured, Anfinsen showed that ribonuclease found its way back to the original shape, implying that there were no other conformations of similarly low energy available to it.

It is remarkable that we only have 20,000 or so protein coding genes when you consider just how large possible protein space is. In this regard, proteins are like English words. There are very few of them when you calculate how many there could be. Sonnet #18 — "Shall I compare thee to a summer's day?" contains 114 words of which 17 are 7 or more letters long. The Oxford English dictionary contains 600,000 or so words of all lengths. There are 8 x 10^9 strings of 7 letters. Few of them have meaning.

Words are a lot shorter than proteins. There are 8 times as many strings of 4 amino acids (20^4 = 160,000) than we have proteins. My guess is that this isn't an accident, because I doubt that most strings of amino acids have a dominant shape (e.g., biological meaning), and even if they did, they couldn't find it quickly enough (the Levinthal paradox again).

How would you prove me wrong? Is the question even meaningful scientifically? I (of course) think it is quite meaningful in a philosophic sense, since it bears on just how probable or improbable life is. The next post will discuss some gedanken experiments which could settle the question (or show that it is unanswerable).

Posted by Stuart Cantrill at 05:03 AM | Permalink | Comments (0) | TrackBacks (0)

Happy Friday everyone, and welcome to this week's batch of research highlights.

Fullerenes:
Buckyballs act just like giant atoms, complete with s, p and d orbitals that are bound to the sphere's hollow centre

Antitumour agents:
Hiding a potent, but insoluble, anticancer drug inside a cage complex represents a new approach to the use of inorganic chemotherapeutics

Self-assembly:
Discrete complexes comprising stacks of up to nine aromatic molecules can be assembled in one step from a few simple building blocks

As for last week, anyone can read the articles for free, but you need to sign up for a free account first.

Neil

Neil Withers (Associate Editor, Nature Chemistry)

Posted by Neil Withers at 05:08 AM | Permalink | Comments (0) | TrackBacks (0)