Yearly Archives: 2008

Chemiotics: We had to destroy the village to save it

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Posted on behalf of Retread

An incredible article appeared last month in the journal Science. If it can be verified and if it applies generally, our conception of just how genes coding for protein are turned on will be radically changed (yes, there are many other kinds of genes other than those coding for proteins). If DNA compaction, nucleosomes, histones, lysine methylation and demethylation, the histone code, nuclear hormone receptors (particularly the estrogen receptor), DNA glycosylase and topoisomerase aren’t old friends have a look at the first comment on this post for the background you need. Don’t worry, there is plenty of chemistry to follow.

Some histone code modifications are reversible, particularly acetylation of the epsilon amino group of lysine. Enzymes acetylating histone lysines are called histone acetylases, those removing it are called histone deacetylatases (HDACs). However, lysine methylation was thought to be permanent until ’04 when several enzymes able to demethylate lysine were found. One such enzyme is called LSD1 (it has nothing to do with the hallucinogen). It removes the two methyl groups from lysine #9 of histone #3 (H3K9me2). If this modification is present on a nucleosome near a gene, the gene is silenced, so the methyls must be removed so the protein it codes for can be made.

The estrogen receptor + estrogen complex bound to the ERE (the estrogen response element – a 15 nucleotide DNA sequence) triggers H3K9me2 removal. The process of demethylation is oxidative (how else would you split a nitrogen to hydrocarbon bond?). Hydrogen peroxide is produced, a loose cannon which oxidizes the juicy electron-rich bases of DNA nearby, forming in particular 8 oxo-guanine, as guanine is the most easily oxidized DNA base. Since 21% of the DNA bases in our genome are guanine, H2O2 doesn’t have far to look. This calls in some fairly heavy artillery (DNA glycosylase to remove the 8 oxo-guanine, topoisomerase IIbeta to unwind the DNA so it can be repaired, the repair enzymes, etc, etc…). Naturally this opens up the compacted DNA structure around the gene allowing RNA polymerase II to do its work transcribing the estrogen responsive gene into mRNA (once the damage is repaired).

So according to this paper, estrogen turns on gene transcription by damaging DNA. This is fantastic (if true). There’s more. The estrogen receptor is but one member of a group of proteins called nuclear hormone receptors. The name comes from the fact that other hormones (progesterone, androgen, thyroid, glucocorticoids, mineralocorticoids) have their own proteins that turn on (or turn off) genes the same way. Subsequently it was found that some vitamin metabolites (vitamin D3, vitamin A) have similar receptors even though they aren’t hormones. The human genome contains 48 such proteins. Less than half of them have known ligands. Those with known ligands have their finger in just about every metabolic pie in the cell.

One final point. It has been estimated that 8-oxoguanine is formed 100,000 times each day in every cell. Perhaps its formation is physiologic rather than pathologic. Where does that leave antioxidant therapy, which has been touted to do everything but cure hemorrhoids? Well, one such trial was done on 29,000 Finnish men at high risk for lung cancer (they were smokers) [New England J. Med. vol. 330 pp. 1029-1035 (1994)] Alpha tocopherol (one antioxidant used in the study) didn’t decrease the incidence of lung cancer, and there was an 18% higher incidence of lung cancer among the men receiving beta carotene (another antioxidant). In medicine, theory is great but data trumps it every time.

Retread

Materials Girl: To sheet or not to sheet

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I don’t know how it is for graduate students, but cheat sheets to me are an ironically great way to study. Over the course of several days, I review every inch of my notes and textbooks, then cover a sheet of paper with two or three columns of formulas and shorthand notes – all written with 0.5 mm lead in miniscule, typewriter-esque handwriting. However, after all that work and cramping of wrist, I essentially remember everything and hardly need the compacted notes.

Inevitably, 97% percent of whatever is on the page never shows up on the exam, and the 3% of material omitted or missed does. (In case it weren’t apparent by the cynical undertone, I’ve lately had back-to-back midterms and have more in the next two weeks. Nothing gets the blood rushing like finishing an exam at 12:57 pm, then sprinting across campus to the next at 1 pm…) On the bright side, nothing beats really knowing that you have a strong grasp of material, even without the chance to prove it on exams. A few years down the road, an undergraduate GPA won’t be worth as much as knowledge. Ideally.

As for previous topics, I’ve decided to go for an internship, given the chance. From what I’ve gathered, extra time on a degree wouldn’t make a great difference, while experience would. Also, a few years in the workforce should take care of the extra debt relatively painlessly… It’d be a nice change from the previous summers of all classes and work, as well as an exciting opportunity to learn – especially because lately my assigned “labwork” has consisted of researching and editing proposals. (As much as more funding for our lab would be nice, I’d prefer to save that aspect of the “real world” for later.) So, I’m crossing my fingers and hoping someone wants me

Charge complete

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Well, it seems only appropriate that I announce our March issue – a Focus on Metals – on National Battery Day. In case you haven’t already seen the new content (alas, it actually went live on Friday, so this post is slightly old news), there are some great pieces inside. In particular, you can ponder the irony of iron being so good for you but tetanus being so bad for you as you read this commentary and this review, which discuss the biological and chemical roles of iron enzymes. Alternatively, you can check out the progress that synthetic chemists are making in designing fluorescent metal sensors in this review. There’s other good stuff as well, but too much to mention in one blog, so you’ll have to check it out yourself.

As a side note (still considering the overlap of metals in biology and batteries), I wonder if anyone is trying to evolve those nanowire-making bacteria to make batteries directly instead? I also spotted this semi-recent paper where the authors are using virus templates to deposit metals for battery electrodes. Seems like the crossover between metals and biology is getting charged up in all kinds of directions…

Catherine (associate editor, Nature Chemical Biology)

Journal journeys: Day 18, Objecting to objectives

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Objective: To write an informative and perhaps somewhat humorous blog entry for the Sceptical Chymist about ‘Objective’ statements that appear at the top of CVs and resumes – without sounding like I’m ranting too much.

As I discussed last week, the habit of including on your CV the fact that you have a driving licence seems a little redundant for certain jobs – such as scientific editors. Sure, if you’re applying to become the next Lewis Hamilton, however, go right ahead, you may even want to put it near the top of your CV – and in bold.

Another observation I would now like to make is that, depending upon the circumstances of your job search, putting an objective statement at the top of your CV could be, for want of a better word, pointless.

First however, here are the situations in which an objective statement is a good and possibly useful feature: (1) you are posting your CV to an online careers site where it may be viewed by all manner of different potential employers, or (2) you are attending a career fair and handing out your CV to a number of different, but I assume related, companies. In these cases, having a generic objective statement that tells people what you are looking for is a good thing, i.e., something along the lines of, ‘…to obtain an R&D position in the pharmaceutical industry that…’.

Now, let’s consider the job applicant who is applying for a specific job – such as that of an associate editor at Nature Chemistry for example. I would assume that because the candidate is applying for that particular job, their objective would be, ‘to obtain a position as an associate editor of Nature Chemistry’. Now, if you ask me, putting that at the top of your CV is pointless, because I assume that if you didn’t want the job, you wouldn’t have applied. It could be argued that this enables the candidate to succinctly sum up their career aspirations – but I think the cover letter is the most appropriate place for that.

The other option is that an applicant sends in a standard CV that has an objective that is not even closely related to the job they’re applying for – such as mentioning something about R&D when applying for an editing job for example. This, to me at least, suggests a lack of attention to detail and hints that the application is somewhat speculative in nature.

So, the best you can hope for by including an objective statement on your CV when applying for a specific job, is that you’ve stated the obvious. The worst, is that the statement bears no relation to the job in question – which doesn’t look good.

In summary, I hope that my blog post meets with your approval and I will follow up with you in a couple of weeks to discuss it with you further.*

Yours sincerely

Stuart

*Every careers-related seminar I went to in the US told me to include a sentence like this at the end of my cover letter, but it just seems a little too earnest to me. If a company really wants to talk to you about your application, trust me, they’ll be in touch…

**I feel I should add a similar disclaimer to that I put in the driving licence post, in that no one will be denied — or indeed selected for — an interview for Nature Chemistry based on whether an objective statement was included on their CV or not.

Stuart Cantrill (Chief Editor, Nature Chemistry)

President of What?

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If you’re living in the United States (or if you’re following the race to the White House from another country/overseas), you’ve probably noticed that – while the presidential candidates have talked about a broad range of important issues – they haven’t spent a great deal of time discussing scientific topics/science policy… You might be interested to learn that ScienceDebate2008.com, a grassroots organization, has been calling for – and has apparently now organized – a presidential debate on science and technology.

While it’s not clear which presidential candidates will attend the debate (April 18th in Philadelphia), I think it could be pretty interesting: science/scientific policy is certainly not the most important issue for many Americans, but I’d personally like to learn more about the candidates’ positions on funding, scientific education, and some of the other topics listed on the ScienceDebate2008.com website.

I’ve been thinking about this topic for a few days, and I’ve come up with a few questions I thought I’d throw out to our readers:

What scientific issue(s) could potentially swing your vote one way or another? For example, could you vote for someone who didn’t ‘believe’ in evolution, or would that be an instant ‘thumbs down’? What about a candidate who mandated that abstinence-only programs were the only kinds of sexual education allowed in public junior high/high schools? What ‘hot button’ issue is so important to you that it would cause you to re-think who will get your vote?

With that in mind, what question (or questions) do you think need(s) to be asked during this debate for it to be useful to the scientific community? Should a prominent scientist be asked to co-host the debate? If so, who has the intellect and the charisma to do it (well)?

Let’s say you won the election and were going to be the next president. What big (science-related) changes/initiatives would you make/fund in your first year in office? For example, would you try to double the NIH and/or NSF budget(s) over the next five years? Maybe you would boost NASA’s budget so that we can put a man/woman on Mars in our lifetime? Would you cut back on research related to bio-terrorism or spend more on this topic? (For the sake of this discussion, let’s assume that you’re so popular/persuasive that you could convince any relevant governmental bodies to do whatever you recommended…)

Looking forward to hearing your thoughts!

Joshua

Joshua Finkelstein (Senior Editor, Nature)

ChemPod 4

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The new chemistry podcast from Nature is now live! – and can be found here.

In this show, we find out how DNA is helping researches build crystals out of nanoparticles, discover a clever chemical trick for manipulating uranium, explore the controversial field of DNA conductivity and talk to chemist Bruce Gibb about re-building life and lab after hurricane Katrina.

Enjoy!

Stuart

Stuart Cantrill (Chief Editor, Nature Chemistry)

Reactions – Stuart James

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1. What made you want to be a chemist?

Science was in the family, and I was encouraged by an excellent chemistry teacher. It seemed a good option after deciding I wasn’t going to follow music. Happily, chemistry turned out to be a very creative career and I haven’t looked back.

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

A musician, touring worldwide and with a recording studio back home. I play guitar and studied as a teenager at the Royal Academy of Music. Music expresses the inexpressible, as they say. I’m also synaesthetic – I see musical sounds as shapes and colours – maybe that’s also why I’ve always been fascinated by it.

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

In at least two ways. On one hand we can help to address the technological challenges facing us – energy, health and cleaner processes – on the other we can provide inspirational, numerate, relevant, and problem-solving education.

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

Mid-week, it would be Einstein. His insights are intellectually astounding and have utterly changed our view of nature. It would be fascinating to get a glimpse into how he got his insights. Weekend, Jimi Hendrix or Frank Zappa.

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

A couple of days ago, together with a PhD student. Very satisfyingly, we found an innovative way to purify a compound which had resisted all the usual methods.

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

The CD would be purely for enjoyment, Sheikh Yerbouti by Frank Zappa, which is a fantastic, hilarious, creative, masterpiece. The book would be something mind-expanding and very long which I haven’t read before, possibly Don Quixote in Spanish, which would probably keep me occupied for 20 years or so…

Stuart James is in the School of Chemistry and Chemical Engineering at Queen’s University Belfast and works on self-assembly, porous liquids and solids, and solvent-free synthesis.

Chemiotics: Introduction and allegro

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[Editor’s note – a new guest contributor, Retread, has joined the team, and should be familiar to some of our readers…]

Feb 13, 2008

“Everything in Chemistry turns blue or explodes”. Only a philosophy major in full hubristic cry could say that to his pre-med chemistry-major ex-roommate. There was some reality to it as the teacher of Chem 101, Dr Hubert N. Alyea, was really a small boy trapped in a professor suit, and usually blew something up in every lecture. Chemistry is still the Rodney Dangerfield of the sciences, important when the demand for taxol for breast cancer threatened to destroy every yew tree in sight, yet largely ignored by its progeny, biochemistry and molecular biology and the press.

Probably every nascent chemist suffers through things like this, but I got more than most, rooming with two philosophy majors as an undergraduate (one of whom was later a Rhodes). It definitely gives you both a thick skin and a more abstract cast of mind.

For who I am and my background go to ChemBark, scroll down the Categories section until you get to Rip Van Winkle open it up and start reading. This where I would have stayed, happily posting now and then and reading and responding to comments. However Paul has other fish to fry (probably his thesis) and ChemBark has developed a definite funereal cast in the 3 months since Paul’s last post. Anyway, Paul got me started and gave me a forum, encouragement and advice, so I owe him at least a good dinner. Thanks Paul.

If contact with budding philosophers didn’t make me somewhat reflective, then following the development of molecular biology from ’62 to the present with the eye and background of a Woodward grad student and medical practice as a neurologist from ’67 to ’00 certainly was enough to do so. This is why future posts will be on things like:

1. Is there really such a thing as causality in cellular biochemistry and physiology?

2. Is organic chemistry easy or hard?

2a. If it’s hard, is math harder?

3. Are there important chemical experiments which we can’t do because the earth isn’t big enough?

4. Is there really such a thing as control in chemical systems with feedback on every component (including the elements providing the feedback)?

5. Does the complexity of cellular chemistry and biochemistry raise questions about the adequacy of chance to bring it about?

That’s for the future. The next post (probably a very long one because of the background required) will be on a recent spectacular paper which, if replicated and generally applicable, will revolutionize the way we think of the control of gene transcription. Thomas Kuhn where are you when we need you?

Stay tuned

Retread

Journal journeys: Day 14, Driven to distraction

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Recruitment for the associate editor positions at Nature Chemistry continues, and although I obviously can’t comment on specifics here, there are some general observations I want to share with you.

No interviews have been scheduled yet, but I want you to imagine a hypothetical scene in which a candidate is sitting across a desk from me and one of my colleagues in the Nature offices in London. We’re about half-way through the interview and the questions continue…

Me: So, if you wouldn’t mind, could you briefly summarize your thoughts on this manuscript for us.

Candidate: Well, although the conceptual novelty is somewhat compromised by the work reported in reference 8, it’s certainly a comprehensive study and represents a significant advance over previous work in this area, so it probably should be sent out to referees to see what they think.

Me: Good, good. So, how’s your parallel parking?

Candidate: I’m sorry, my what?

Me: Parallel parking – oh, never mind. OK, minibuses, have you ever driven a minibus?

Candidate: What? A minibus? Erm, no… no I haven’t – why?

Me: Hmm. Oh dear, that could be a problem. Now, let me see, yes, you’re driving at 47 mph down a country lane and it rained heavily about 12 hours earlier, what’s the safe stopping distance?

Candidate: I beg your pardon.

Let me just point out now, that exchanges of this kind will not feature in the interviews. No one will be asked about their driving skills or associated knowledge. And I can guarantee this in spite of the fact that most of the people in the UK (including some, but not all of the Nature Chemistry candidates), proudly include on their CVs that they have a driving licence.

To be fair, I used to put this invaluable nugget of information on my CV as well, until one day I suddenly realized that it really wasn’t all that important for the jobs I was applying for… i.e., if you can analyze the ins-and-outs of an asymmetric synthesis paper, I don’t really care if you can do a three-point-turn or not.

I think it’s just a hangover from what we were all told at school – I think that’s where I picked up the habit. Sure, it does no harm (and no one will be denied — or indeed selected for — an interview for Nature Chemistry based on whether this was included on their CV or not), but unless it is directly relevant to the job, I don’t see the point.

Please note, however, that I am not a recruitment specialist or hiring manager (or whatever you call those people) and perhaps I am missing something important – so I’m not offering professional advice here, leave this piece of information off your CV at your own peril. (Perhaps that was why the Royal Society of Chemistry turned me down?).

I don’t remember seeing driving qualifications on any of the non-UK CVs, but that’s not to say they don’t have their own problems. If I get a minute away from websites, podcasts, hiring and Nature Nanotechnology manuscripts, I’ll be back to tell you about them…

Stuart

Stuart Cantrill (Chief Editor, Nature Chemistry)

Chemistry in fantaseo

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I just happened across this delightful science article, which discusses some of the advanced physics that would allow fairy tale things like people climbing each other’s hair and stealing each other’s voices to be true, or potentially true.

I always like a good science-is-stranger-than-fiction story, but what I found amusing about the article is that the ‘not-true-to-life’ aspect that the author chose to focus on, for example in the case of the little mermaid, is not that:

a) there is a mermaid living under the sea who

b) gets her body magically transformed (her fins turned to legs, but also her lungs changed to breathe air, and her head changed to a dino size in relation to her body (you know what I mean if you’ve seen the movie))

c) by a witch who

d) communicates with eels.

Rather, the author suggests only that it’s weird that this witch would also be able to somehow capture the girl’s voice (and, it’s not clear to me why the winds of the Caspian Sea need to be involved if this witch has indeed just developed some advanced technology).

However, I don’t mean to disparage the article – baby steps, right? And anyway, I’m excited about the prospect of my own flying carpet.

On a related note, there are many chemical mysteries to be solved in fairy tales: For example, what kind of poison did the Queen give to Snow White that put her into a sleep/coma but immediately reverses when she was kissed by a prince? What kind of pigmentation would make the Wicked Witch of the East’s skin green (and, for a biological mystery, how did she get it?)? What was in the mushroom that made Alice shrink or grow? Any and all explanations (or additional mysteries) welcome!

Catherine (Associate Editor, Nature Chemical Biology)