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About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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December 30, 2010

Another Cold-Weather Recipe: Chicken Pot Pie

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Posted by Derek

Here, as promised, is another dish for weather like the present. It takes some time, but if the snow is coming down and the wind is rattling the windows, you may well have some. You'll need, at a minimum: a chicken, vegetables (carrots, celery, onions, peas, etc.), some flour and milk, and some source of pie crust, either home-made or bought. (Note that if you're going to make your own crust, that needs to be started early in the process so it'll be ready to roll out - see below. If you're a make-your-own-crust type, though, you probably already knew that, though).

First take the chicken (up to a 3-pound / 1.4kg one) and simmer it in water (to cover). I season this with salt, black pepper, and a bay leaf, but you can modify this to taste - you're going to have extra chicken broth when this is over (no bad thing!), so season it the way you like it. A half hour should take care of the bird - take it out of the broth and let it cool down enough to handle, then remove the skin and pull the meat off the bones. You'll need to cut the larger pieces down to size - 1 to 2 cm on a side, say. I usually put the chicken pieces into a large bowl; you'll be adding more to it in a few minutes.

Now, the vegetables: peel and cut up 3 or 4 medium-sized carrots into similar-sized pieces as the chicken, and do the same with two large stalks of celery. For the onions, you can chop up a large one, or do what I often do - take half to 3/4 of a bag of frozen pearl onions (8 to 12 oz., 230 to 340 g) and let them thaw while working on the other vegetables. If you like mushrooms, you can also add some to taste; I often do. If they're fresh, you'll want to saute them along with the other vegetables in the coming step, or you can add canned ones at any point.

Take the cut vegetables and saute them in a large pot in oil over medium-to-high heat for five minutes or a bit more - you just want to get them started cooking, and not brown them or make them actually soft. You can add salt and black pepper as desired at this point. Then turn them out into the same bowl as the cut chicken. Take the same pot and melt about 4 tablespoons butter (50g) in it, then add 1/2 cup flour (which I think should be about 60 to 65 g), and stir that in. Cook the butter-flour mixture (which will be pretty solid) for a minute or two, then add 2 cups (475 mL) of the chicken broth you have, whisking it in to break up that flour lump, followed by 1 1/2 cups of milk (350 to 360 mL). Continue to whisk this around vigorously while it's heating - it'll thicken into a sauce (more specifically, into a béchamel sauce).

This is a good time to get the oven going - heat it to 400F, or 200 to 210C. Now Season the sauce with some more ground black pepper and about a half teaspoon of dried thyme (0.75 g), then add the vegetables and chicken, and stir to mix everything. At this point, you can add a cup of frozen peas, as they are, to the mix - they'll come out festively green at the end. If you have some fresh parsley on hand, you can chop a small handful and add it now. It goes well, but I've made it without as well, and it's still completely edible.

This mixture is ready to go into whatever sort of form you wish your chicken pot pie to take. Store-bought pie crust, the kind that comes refrigerated and rolled up, can be used to line a large oven-proof bowl. You than empty the pot pie mixture into that and use the second crust in the package across the top. (Some people like a bottom/side crust, others don't). You can use a wider, shallower pan and just have a top crust, or break the recipe up into individual oven-proof bowls. Your call! They all work fine.

If you're going to go all the way and make your own crust, then I'm going to have to refer you to your favorite recipe for it, since I rarely make my own, to be honest. (I wouldn't recommend making your first one at the same time you're doing all the rest of this). Remember, though, jome-made pie crust has to be refrigerated for a half hour or so to get it ready to be worked. You can also use a biscuit topping, if you've got a recipe you like for that - I haven't tried it myself, but it seems like it would work fine.

Cook the pie at the above-mentioned 400F until the crust is starting to brown. Depending on the format of your pie (or pies, if you broke it up into smaller servings for a group), this could be as short as 20 minutes or more like 35 to 40. And there you have it! And as a side effect, you now have some chicken stock to freeze for later on. Enjoy!

Comments (14) + TrackBacks (0) | Category: Blog Housekeeping

December 28, 2010

A Cold-Weather Recipe, By Request: Onion Soup

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Posted by Derek

If there's big pharmaceutical news going on right now, it hasn't reached me. So in the spirit of taking time off, here are some things I've been making here at home while the wind rattles the windows.

First up is French onion soup. I use pretty much the procedure that the Cooks Illustrated people recommend. Take half a dozen onions (this should be a bit over 3 lbs, or 1.5 kg) and slice them fairly thinly. The Cooks people recommend red onions, and those certainly work well, but I've used all sorts (and mixtures of whatever's on hand). Now comes the only time-consuming part: cook these in a pot with butter (2 tablespoons, or about 30 grams) over medium-to-low heat, stirring frequently, until they're quite dark but not burnt. This will take at least half an hour, and probably more. If you're using a conventional pot (not nonstick), you'll have a lot of stuff stuck to the sides, so be careful that it doesn't burn. This is the key step in the whole preparation: well-browned onions are the crucial ingredient, without which all is lost.

Now add a mixture of beef broth (2 cups, 500 mL) and chicken broth (6 cups, 1500 mL). I sometimes have the latter around frozen from previous chicken preparations, otherwise, you can use canned. Beef broth I almost never have around, for one reason or another, so that's almost always canned. (Note - using all canned beef broth makes a fairly nasty soup, while using all chicken broth makes an edible, but rather chicken-centric one). This step will loosen up all the caramelized onion stuff and get things into suspension, if not into solution. You can also add a half cup or so (125 mL) of red wine at this point if you like. Season it all with dried thyme, salt, and pepper to taste, add a bay leaf, and simmer the mixture gently for at least fifteen minutes. (If it goes longer, you can add a bit of water to bring the volume back up). Check the taste at this point - you might like it with more of a bite, in which case a few mLs of balsamic vinegar added to the pot will help out.

You can have this as is, or go the traditional gratineé method, with toasted bread and cheese on top. I use whatever's on hand in the bread department, just making sure that it's cut fairly thick and is well toasted, and then add some sort of Swiss-ish cheese - your choice. (You can even go as far, and as non-traditional, as mild Provolone, but I don't think that sharp cheddar (for example) would be a very good idea). The best way to do all this is probably to put the soup in some sort of heat-resistant bowl, plop in the bread, cover that with cheese, and run the whole thing under a broiler.

This, to me, is one of the best meals for very cold weather - I can't imagine eating it in July. Next post: chicken pot pie.

Comments (17) + TrackBacks (0) | Category: Blog Housekeeping

December 27, 2010

Weather Delay

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Posted by Derek

My company closes down between Christmas and New Year's (or at least it has the last couple of years), and I have to tell you that this is a good thing today. We've had between one and two feet of snow, starting late yesterday, and it's now being blown all over the landscape by 40 mile-per-hour winds. Commuting in to work does not appeal.

Neither does even setting foot outside, actually - I haven't even put my hand on a doorknob today. Instead, I'm teaching my kids how to play table tennis, and they're whipping me at Mario Kart. Dinner last night was a big pot of French onion soup, which I've always considered an excellent response to weather like this, and tonight I'm making a chicken pot pie from scratch. Recipes on request!

Comments (14) + TrackBacks (0) | Category: Blog Housekeeping

December 22, 2010

Holiday Break

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Posted by Derek

Starting today, I'm going to switch over to Holiday Blogging Hours. Unless something gigantic happens, there won't be anything else here until Monday at the earliest. And blogging next week will be spotty as well, while I lounge around with the family. I've already been contributing on the cookie-baking, tree-decorating, and shopping fronts, and plan to start working soon on the important sleeping-in-late effort. With any luck, I'll have a couple of clear nights over the vacation to break out the telescope. The Christmas lights tend to brighten up the sky background a bit during this season, but one takes what one can get.

I hope that everyone out there who's celebrating has a good break, too. See you next week, and after that, next year. . .

Comments (18) + TrackBacks (0) | Category: Blog Housekeeping

December 20, 2010

Putting Some Numbers on Peer Review

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Posted by Derek

Since we've been talking about peer review on and off around here, this paper in PLoS One is timely. The authors are putting some numbers on a problem that journal editors have long had to deal with: widely varying reviews from different referees for the same exact paper.

It's a meta-analysis of 52 studies of the problem reported over the last few decades. It confirms that yes, inter-reviewer reliability is low. The studies that report otherwise turn out to have smaller sample sizes and other signs of lower reliability. The question now is: to what extent is this a problem?

One of the studies they quote maintains that too high a level of agreement would also be the sign of a problem (that some of the reviewers are redundant, and that the pool of referees might have been poorly chosen). I'm willing to think that total agreement is probably not a good thing, and that total disagreement is also trouble. So what level of gentlemanly disagreement is optimal? And are most journals above it or below?

FIguring that out won't be easy. Some journals would really have to open their books for a detailed look at all the comments that come in. I assume that there are editors who look over their reviewers, looking for those that tend to be outliers in the process. (Um, there are some editors that do this, right?) But that takes us back to the same question - do you value those people for the perspective they provide, or do you wonder if they're just flakes? Without a close reading of what everyone had to say about the crop of submissions, it's hard to say. Actually, it might not be easy, even then. . .

Comments (21) + TrackBacks (0) | Category: The Scientific Literature

December 17, 2010

Jobs Roundtable Recap

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Posted by Derek

And here's the recap for the jobs roundtable week, up at ChemJobber. There's been a lot of interesting stuff posted, and I'm glad to have been able to help call attention to it all. . .

Comments (15) + TrackBacks (0) | Category: Business and Markets

Politics in the Lab

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Posted by Derek

Man, have I been avoiding this topic. But I think it's time. Slate recently published this piece on the political affiliations of scientists, with the provocative sub-head: "Most scientists in this country are Democrats. That's a problem."

Is it? Is that even true? The piece is based on this survey by the Pew Foundation, which was conducted in 2009 by surveying over 2000 members of the AAAS. Now, I'm trying to come up with the figures, but my strong impression is that the organization skews pretty strongly academic, which might account for some of the numbers. (Science, for example, runs articles like this one, explaining the mysterious world of industry to job-seekers.

So I'm not sure if the Pew numbers are accurate. Still. . .for what it's worth, they come out like this: for self-described party affiliation, Dem/Rep/Ind, the general public was 35/23/34, and the sample of scientists was 55/6/32. And in more philosophical terms, as self-identified liberal/moderate/conservative, the general public was 20/38/37, and the scientists were 52/35/9. Those are some pretty stark differences - correcting for sample bias would probably even things out some, but I can't imagine it would be enough to take care of a gap that large.

The Slate piece says that this is indeed a problem:

During the Bush administration, Democrats discovered that they could score political points by accusing Bush of being anti-science. In the process, they seem to have convinced themselves that they are the keepers of the Enlightenment spirit, and that those who disagree with them on issues like climate change are fundamentally irrational. Meanwhile, many Republicans have come to believe that mainstream science is corrupted by ideology and amounts to no more than politics by another name. Attracted to fringe scientists like the small and vocal group of climate skeptics, Republicans appear to be alienated from a mainstream scientific community that by and large doesn't share their political beliefs. The climate debacle is only the most conspicuous example of these debilitating tendencies, which play out in issues as diverse as nuclear waste disposal, protection of endangered species, and regulation of pharmaceuticals.

I think that's a reasonable summary, especially if you're the sort of person who thinks about politics all the time. But that's a key consideration: not everyone does. It's hard to remember this if you're interested in politics yourself, and if you spend a lot of time following current events and world affairs. Politics, and political ideology, is just one template people use to view the world. Everything can be fit into it one way or another, and it's fun to keep score. I imagine the point-totaling sound as being like a pre-digital pinball machine: chunk-chunk-chunk-ding! This side scores, that side scores.

But how much of this overlaps with what goes on in the labs? The examples in the quoted paragraph certainly do, but there are many less politically contentious issues that are scientifically important. It's hard to fit disagreements over dark matter or RNA's role in early life forms into a left/right framework, much less intramural spats like the structure of the norbornyl cation, the usefulness of total synthesis, or how much palladium you really need to do a metal-catalyzed coupling.

In the end, I think the "it's a problem" conclusion of the Slate article should be amended to "it's a problem if you measure everything by politics". That's a temptation that should be avoided, as far as I'm concerned. Orwell was right to consider a world where everything was subordinate to political concerns as a nightmare. And while I have strong political opinions myself, and follow the whole business much more than I follow any traditional sport, I still would like to have some areas free of it.
.

Comments (63) + TrackBacks (0) | Category: General Scientific News

The Avastin Decision: A Reality Check

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Posted by Derek

So the FDA did indeed rescind their conditional approval for Avastin in metastatic breast cancer. I think that this was the right thing to do, given that the weight of the evidence now says that it doesn't do any good in that situation. Problem is, there are a lot of people trying to make political points off this decision, saying "See? We told that Obama's health care plan would lead to this. Life-saving medical breakthroughs, pulled because some bureaucrat says that they're too expensive".

Wrong. And I say this as someone who still thinks that the health care plan is a bad idea, poorly implemented. It would be good if other people opposed to it could resist the any-weapon-to-hand temptation in this case, but that's politics for you. (I'd hoped back in August that we could avoid this stuff, but that was always a long shot). The FDA is not in the business of considering costs, just safety and efficacy. And the balance between those two, in the case of hard-to-treat metastatic breast cancer, is not in Avastin's favor. If we're going to speed things up with conditional approvals, we're going to have to be able to take them back when they don't work out. This one didn't.

Here's some good background from WebMD on this decision, and more from Science-Based Medicine on the clinical evidence. That's the evidence we have, and that's why I think this was the right decision.

Comments (9) + TrackBacks (0) | Category: Cancer | Regulatory Affairs

December 16, 2010

Science Jobs Roundtable - Day Four

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Posted by Derek

The Thursday installment of the science jobs roundtable is up over at ScienceGeist. This time the topic is how to fund research so that it has a greater chance of generating new employment - a tough topic, and I'm not sure I agree with all the possible cures proposed, but check it out and see what you think.

Comments (13) + TrackBacks (0) | Category: Business and Markets

December 15, 2010

What A Paper Doesn't Have In It

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Posted by Derek

So, should I apologize for the tone of yesterday's post? I'm not ready to yet, and I'll explain why.

Here's a general rule: if you find yourself having to make excuses for a scientific paper, for the key experiments that weren't done and the rationales that don't appear, then something is wrong. A paper shouldn't make you have to assume that the authors will get around to running Experiment X and Comparison Y and Test Z, and put that in their next manuscript. (If this makes you think of the recent arsenic bacteria controversy, you're right on target). Anything like that which immediately comes to mind should be in the first manuscript. If the authors haven't put it in there, then it's the job of the referees to tell them to go back and do it. And whoever refereed this paper did an incompetent job.

Now, a quick technical note. It's true that medium-sized rings can form isolable atropisomers in some cases. (An atropisomer, for those who aren't chemists - or chirality geeks - is a compound that can exist as two mirror-image forms just through some sort of constrained movement of its parts. A putatively flat compound that comes around and wraps over itself like a screw thread is one example, as is one with a bond that should be freely rotating but it blocked by large side chains from doing so).

Problem is, this compound sure doesn't look like one of those cases. It has no bulky groups that have trouble getting out of each other's way, and it has no helical chirality. The only thing it has, to my eyes, is a nitrogen that could only lead to new isomers if its barrier to inversion were really, really high - and it shouldn't be. For nevirapine, there really should be no way to isolate such an isomer at room temperature. If anyone can provide evidence for isolable atropisomers in a system as small and lightly substituted as this one, I'll certainly consider eating my words - but not until then.

But that brings up a larger point. This is actually one of the things that makes me think this paper is bogus: the presence of such a compound really would be the big selling point of the manuscript, if the authors had thought about it. Instead, their main focus is on how the structure turns out to be a natural product (which I have trouble believing, too),and not on the bizarre nature of it being chiral. The chirality, frankly, seems to be an afterthought, the way things are written. The word "atropisomer" does not make an appearance. References to the other dibenzo ring systems that have shown this interesting phenomenon (which were worth papers all their own) are not cited. There is no mention of a nitrogen inversion. (If that were the explanation, you'd also expect that heating up the sample would eventually start flipping the molecules past that barrier and removing the optical activity - but there's no mention of any such thing). You'd never know that there was something interesting going on, because the authors give us no reason to believe that they knew that, either.

It would also be quite interesting, if you could have such a thing as an optical isomer of nevirapine, to see what its activity would be on its enzyme target, reverse transcriptase. And if nevirapine could exist as enantiomers, how about running the synthetic material down some chiral columns to see if you could resolve it? Then show that your new optically active stuff is only one of those peaks; that would be pretty convincing. Not done, not done, not even mentioned, etc.

Here's another consideration: as mentioned yesterday, I don't think that this structure has been given very good characterization (the X-ray data seem insufficient to talk about chirality). One of the comments to yesterday's post wondered why the authors didn't show HPLC traces with and without a spike of the authentic drug material. That's an excellent idea, and it's something that would be worth showing in an NMR spectrum, too. Claiming that you found nevirapine in a plant is quite weird - you'd want to really hammer down the fact that everything is identical. But these experiments haven't been done, either.

Allow me to mention one more oddity. The authors actually make reference to "optically active nevirapine" (their footnote #10), but the reference they cite (the original paper from Boehringer Ingleheim) does not, as far as I can see, mention any such thing. And that's because no one has ever mentioned any such thing, and that's because I don't think it exists, outside of (just maybe) a low-temperature NMR experiment.

No, I'm still not buying this. I'm upset with the authors for having proposed such a thing with such thin evidence, but I'm really more upset with the editors of what is supposed to be a reputable journal for publishing it.

Comments (27) + TrackBacks (0) | Category: The Scientific Literature

Chemistry Jobs Roundtable: What About Tenure?

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Posted by Derek

The latest post in the week-long blog roundtable on chemistry jobs is up over at Chembark, and it looks at the academic side: is tenure useful? If so, do its disadvantages outweigh the benefits? What would happen if we ditched it (and could we)?

Comments (14) + TrackBacks (0) | Category: Academia (vs. Industry) | Business and Markets

Chiral What? Chiral How?

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Posted by Derek

Thanks to an email from a reader, I can bring you this very weird paper from Tetrahedron. The authors claim to have extracted a local plant and isolated nevirapine, (sold as Viramune by Boehringer Ingleheim as a reverse transcriptase inhibitor for HIV).
nevirapine.png
That's kind of odd. I'm no natural products expert, but I've sure seen a lot of them over the years, and that framework (and the N-cyclopropyl) don't look so likely to me. But hey, plants do odd things. That's not what's really puzzling about this paper. No, what's had me staring at it this morning is the claim that, in contrast to the marketed drug, this stuff is optically active nevirapine.

Say what? Try as I might, I can't see any plausible way that that's a chiral compound. The authors seem to think it is, though. They claim optical rotation, somehow, and then say that "The detailed structure and stereochemistry of compound 1 was established unambiguously by single crystal X-ray crystallography." But hold on - that's not as easy as it sounds. Getting absolute configurations from the X-ray data of light-atom-only molecules takes special efforts, and I don't see any being taken (molybdenum X-rays, direct methods, no talk of anomalous dispersion, etc.)

I'm just not willing to see that nitrogen atom as a source of chirality - if it were, shouldn't that be the focus of this whole paper? Instead, the authors just blithely tell us how neat it is that they've isolated the chiral material. In fact, they find it so neat that they tell us two times in a row:

This is a very interesting discovery that naturally occurring optically active nevirapine has been biosynthesized in the seeds of C.viscosa and the optically inactive nevirapine was designed as a selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. It is also a remarkable finding that the seed of C.viscosa is the source of optically active nevirapine, which was also designed and synthesized before its isolation from natural source.

This sounds like some sort of lunatic patent-busting exercise, to be honest. And it sounds as if someone doesn't know what a chiral compound is. And that whoever reviewed this for Tetrahedron was incompetent. And that the editor who let it through should be a least a little bit ashamed. Well?

Comments (73) + TrackBacks (0) | Category: Infectious Diseases | Natural Products | The Scientific Literature

December 14, 2010

Too Many PhDs, Revisited

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Posted by Derek

Part Two of the week-long blog roundtable on chemistry jobs is up over at Just Another Electron Pusher. This one is a data-rich post on the topic of whether there are too many science PhDs being turned out. Or are there just too few jobs for them? Can we tell the difference between those two situations, and does it matter? Well worth a read.

Comments (43) + TrackBacks (0) | Category: Business and Markets

The Solid Phase

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Posted by Derek

Looking over the chemical literature with an RSS reader can really give you a sense of what the hot topics are, and what's cooling off. Remember when it seemed as if every third paper was about ionic liquids? You still see work in the area, but it's nowhere near as crazy as it was. (I had a colleague come by my office the other day and ask "Did anyone ever find out what to do with those things?") Similarly, gold catalysts have been all over the place in recent years, but seem, to my eye, to be calming down.

Some of these things are research areas that look promising, but die off when their limits become apparent. Some of them are almost sheer fads, with papers coming out from all sorts of odd places because the authors want to get in on the hot, publishable topics while they can. Others keep going because the topics themselves are important but ver hard to exhaust (metal-catalyzed couplings come to mind).

And there are areas that keep going in the literature because they look like they should be important and useful, and eventually will, but no one can quite get them to either work generally enough or get people to recognize that they do. The metal-catalyzed coupling literature was in this shape back in the 1970s and into the 1980s - there were a lot of disparate reactions that you could do with palladium, but none of them had exactly taken over the world. My vote for a current field in this protostar state is engineered solid-phase catalysis.

That may sound odd, since work on solid-phase catalysts has been going on for decades, and is of huge industrial importance. But many of the important catalysts have been arrived at either by luck or by an awful lot of hard slogging. The field is complicated enough - fiendishly so - that it's hard to draw general conclusions. If you have a good solution-phase catalyst, how do you make a solid-supported variety that works just as efficiently? Well. . .if you really want one, you make about a zillion variants and hope for the best, as far as I can see.

Part of the problem (as with the metal-catalyzed coupling world) is that there are just so many variables. The solid supports alone are enough to keep a person occupied for life, what with all the various aluminas, silicas, zeolites, polymers, mesoporous engineered thingies, and so on. Then you have the uncountable schemes for linking these surfaces to active catalysts - what functional groups to use, what density things should be on the surface, what distance you need between the surface and the catalyst, etc. And just linking up to the known catalysts is no light work, either, since most of these things were not made with convenient handles hanging off them.

As we get better at making (and characterizing) new kinds of surfaces and new kinds of macromolecular assemblies, we might start to get our hands around this subject. For now, though, it seems to be mostly in the descriptive stage: papers are of the "Hey, we made this thing and here's what it does" variety, with further work in the series being "Hey, remember that stuff we made? Turns out you can do this with it, too - who knew?" What you don't see, or not too darn often, is a paper describing the general principles of these processes. For the most part, we don't know them yet.

But if I had to pick an area that will eventually blossom into a host of applications, this would be high on the list. It's a mixture of surface chemistry, materials science, nanotechnology, and organic synthesis, and it's got a lot of promise. But then again, it's had a lot of promise for a long time now. . .

Comments (9) + TrackBacks (0) | Category: Chemical News | The Scientific Literature

December 13, 2010

Big Pharma's Lost Stock Market Decade

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Posted by Derek

Talking about Pfizer's stock price the other day let several people to note in the comments that it's not just PFE stock that's had a bad ten years: a lot of other big drug companies have, too, including some (like Lilly) that have very much declined to grow by merging. And it's true, as this chart will show.
drug%20company%20stock%20chart.jpg
This is a sampling of some big US-based pharma companies that have been around during the whole ten-year span. Note that J&J is actually ahead of the index (in red), and it and Abbott are the only two that can claim that distinction. (They're also the only two on the list with a significant medical devices/diagnostics presence - coincidence?)

The pure drug plays have all been pretty rough. Merck, Bristol-Myers Squibb, and Lilly are right down there with Pfizer. What I was trying to get across the other day, though, was not that Pfizer had been awful relative to its peers, but that it's been just as bad. All that merger activity, all that turmoil, has come down to this: same lousy performance as the other big companies. What, from an investing standpoint, has it done for anyone?

Now (as was also pointed out in the comments last week), these charts neglect reinvested dividends, but an S&P index fund's performance would also show some effect from that, too (although not as large as for some individual stocks, for sure). Another big point: we'll never be able to run the control experiment of dialing back the time machine and letting Pharmacia/Upjohn, Warner-Lambert, and Wyeth all stay un-Pfizered. (Not to mention what Pfizer might be were it to have remained un-super-sized). There are too many variables. All we can say is that there's no evidence that any of the big boardroom-level strategies have been superior to any other.

But given the way drug discovery has been going the last ten or fifteen years, it's hard to see anything making such charts look good, mergers or no mergers. That brings up a causality problem, too - it's important to remember that while mergers don't seem to have been doing any favors for drug research, the existing problems of drug research are what have led to many mergers. What was it that David Foster Wallace once said - that the definition of a harmful addiction is something that presents itself as the cure for the problems it's causing?

Update: in case you're wondering if this is just an effect of starting ten years ago (when the market was much livelier), you can use that Google Finance link to move the starting point back. From what I can see, you have to go back to 1994 or 1995 to find a point at which most of the drug stocks would have outperformed the S&P 500 (and as that last-ten-year chart shows, all of that happens early). Merck lags for a long time, and Bristol-Myers Squibb and Lilly still aren't above the line even if you start in the mid-1980s.

Comments (32) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

Chemistry Jobs, Present and Future

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Posted by Derek

I'd like to call attention to a week-long blog roundtable on scientific jobs and hiring that's starting today. The first installment is up at Chemjobber, and it's excellent reading. How did the employment picture in chemistry get into this shape? And are there any reasonable ways out of it?

We've talked about that over here in the past, but today I encourage everyone with an interest in these topics to head over to ChemJobber and add their ideas to the comments. I'll be putting up pointers to the other posts in the series during the week as well.

Comments (3) + TrackBacks (0) | Category: Business and Markets

December 10, 2010

Have Pfizer's Investors Had Enough?

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Posted by Derek

It's taken a while, but have Pfizer's long-suffering investors finally had enough? FiercePharma has a roundup of stories that suggest that some of the institutions are upset over the abrupt departure of Jeffrey Kindler this past weekend. The quote that leaps out is one from an unnamed hedge fund manager who calls the current board "value destroyers".

Who'd disagree? But who would think that it would take this long for such people to realize the value that's been shredded over the years by Pfizer's acquire-acquire-acquire strategy? Here's ten years of Pfizer versus the S&P500. Up until 2004, with a couple of brief excursions, Pfizer stock basically tracks the index. After that, it lags badly. Over a decade of hard work on Wall Street, analyzing Pfizer's prospects, peering into their books, assessing their portfolio, weighing the chances for each drug, the ramifications of each acquisition: in vain. All in vain, because you'd have done far, far better with the money by parking it in an index fund and walking away to do something more meaningful with your time. Not that you wouldn't have lost money doing that; the S&P 500, damn it all, is down over a ten-year span. But you'd have lost a lot more if you'd listened to Pfizer's press releases or anyone who recommended that you buy their stock.

I've been complaining here about Pfizer's strategy since at least 2003, but it's not like I'm happy about being right. So many people have had their lives disrupted by Pfizer's acquisitions, and there's been so little return on all of it that it's hard to feel good about anything associated with the company's recent history.

And now that all these gigantic deals have been done, the employees have been jerked around, and the facilities closed, what are these big investors proposing to do about it? An angry committee has been formed to discuss strategic barn-door-closing initiatives, but the horses are over the horizon.

Comments (54) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

December 9, 2010

The Escondido House of Explosives Goes Up - Live

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Posted by Derek

A reader has just sent me a link for a live video feed of the the (theoretically) controlled burn of the explosives-laden house that we were talking about here the other day. Word is that they're scheduled to start at between 10 and 11 AM PST (2 to 3 PM on the East coast, 1800-1900 GMT).

Prime viewing time! know that this answers the hopes of many people, and I'm happy to send this information along.

Update: well, it looks as if things were, in fact, pretty well controlled. The reporters on the scene did hear a few loud bangs from inside the house, but nothing roof-raisingly major seems to have gone up, which is probably all for the best. So until the next explosives-obsessed bank-robbing lunatic is reeled in, this will have to tide us all over.

Comments (23) + TrackBacks (0) | Category:

So What's Going On With Peer Review, Anyway?

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Posted by Derek

I have a larger comment, sparked by the controversy over the NASA-arsenic-bacteria paper in Science. But it's not just about that one. It's about the "reactome" paper (also in Science and now retracted), the hexacyclinol synthesis published in Ang. Chem., and others. There have been, I think it's fair to say, a number of very arguable papers published in very high-profile journals in recent years. What's going on?

I want to make it clear that I'm not upset about journals published "out-there" work. In fact, I wish that there were a bit more of it. But at the same time, if you're going to go out there on the edge, you'd better have some solid stuff to report when you come back and write up the paper. Extraordinary claims really do require extraordinary evidence, and that's where things seem to be breaking down.

Peer review is supposed to catch these things. That reactome paper had chemists rolling their eyes as soon as they saw the synthetic schemes in it, and asking if anyone at the journal had thought to call someone who knew organic chemistry during the review process. This latest arsenic paper has other specialists upset, for different reasons (and, to be sure, for reasons that don't require much scientific specialization at all, as detailed in my post after I'd given the paper a close reading). But that hexacyclinol paper appeared in a chemistry journal, and had (one assumes!) been reviewed by competent chemists. How, then, could it have been published to immediate howls of derision about the quality of the evidence in it?

I also want to make clear that I'm not talking about some of the other categories of bad papers, such as the things are are probably true, but of little interest to anyone. And in the probably-not-true category, lower-ranking journals let not-so-good stuff through pretty often. I've been hard on Biorganic and Medicinal Chemistry Letters here before, among other journals, for publishing things that appear to have been incompetently reviewed. But these journals aren't Science or Nature, and the whole point of prestigious journals is that the things that appear in them are supposed to be important, and they're also supposed to be thoroughly vetted.

Is it the push to land the big papers that will make a big splash? Does that cause people in the editorial offices to bend the rules a bit? The official answer from every journal editor that's ever lived to such questions has been "Of course not!", but you have to wonder. Is it a problem with how they're assigning papers for review - who they go to, or how seriously the reviews are taken when they come back? I really don't know. I just know that we seem to be seeing a lot of embarrassing stuff in the literature these days. It's not supposed to work that way.

Comments (40) + TrackBacks (0) | Category: The Scientific Literature

December 8, 2010

NASA's Arsenic Bacteria: A Call For Follow-Up Experiments

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Posted by Derek

Since the posts here on the possible arsenic-using bacteria have generated so many comments, I'd like to try to bring things together. If you think that the NASA results need shoring up - and a lot of people do, including me - please leave a comment here about what data or new experiments you'd want to see. I'll assemble these into a new post and try to get some attention for it.

The expertise among the readership here is largely in chemistry, so it would make sense to have suggestions from that angle - I assume that microbiologists are putting together their own lists elsewhere! I know that several readers have already put forward some ideas in the comment threads from the earlier posts - I'll go back and harvest those, but feel free to revise and extend your remarks for this one.

So, the questions on the table are: do you find the Science paper convincing? And if not, what would it take to make it so?

Comments (38) + TrackBacks (0) | Category: Analytical Chemistry | General Scientific News

Fluorination Without Tears. Or Panicked Shouts.

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Posted by Derek

One of the comments to this post brought my attention to this paper in JACS on a new fluorinating agent. I just finished writing a column on fluorinated drugs for Chemistry World, so the subject is on my mind.

I have to say, this looks like it could be a very useful reagent. I've never worked with any arylsulfur trifluorides, but that looks to change soon, since I'd guess that this stuff will shortly be commercialized. An air-stable, non-runaway reactive fluorinating reagent would hit the spot. It would be fine with me if I never open another bottle of DAST again, and my experiences with the likes of xenon difluoride haven't been wonderful, either. If anyone gets a chance to try this compound out, let us know if it's all it's billed to be!

Comments (7) + TrackBacks (0) | Category: Life in the Drug Labs

December 7, 2010

Arsenic Bacteria: Does The Evidence Hold Up?

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Posted by Derek

It's time to revisit the arsenic-using bacteria paper. I wrote about it on the day it came out, mainly to try to correct a lot of the poorly done reporting in the general press. These bacteria weren't another form of life, they weren't from another planet, they weren't (as found) living on arsenic (and they weren't "eating" it), and so on.

Now it's time to dig into the technical details, because it looks like the arguing over this work is coming down to analytical chemistry. Not everyone is buying the conclusion that these bacteria have incorporated arsenate into their biomolecules, with the most focused objections being found here, from Rosie Redfield at UBC.

So, what's the problem? Let's look at the actual claims of the paper and see how strong the evidence is for each of them:

Claim 1: the bacteria (GFAJ-1) grow on an arsenate-containing medium with no added phosphate. The authors say that after several transfers into higher-arsentic media, they're maintaining the bacteria in the presence of 40 mM arsenate, 10 mM glucose, and no added phosphate. But that last phrase is not quite correct, since they also say that there's about 3 micromolar phosphate present from impurities in the other salts.

So is that enough? Well, the main evidence is that (as shown in their figure 1), that if you move the bacteria to a medium that doesn't have the added arsenate (but still has the background level of phosphate) that they don't grow. With added arsenate they do, but slowly. And with added phosphate, as mentioned before, they grow more robustly. It looks to me as if the biggest variable here might be the amount of phosphate that could be contaminating the arsenate source that they use. But their table S1 shows that the low level of phosphate in the media is the same both ways, whether they've added arsenate or not. Unless something's gone wrong with that measurement, that's not the answer.

One way or another, the fact that these bacteria seem to use arsenate to grow seems hard to escape. And they're not the kind of weirdo chemotroph to be able to run off arsenate/arsenite redox chemistry (if indeed there are any bacteria that use that system at all). (The paper does get one look at arsenic oxidation states in the near-edge X-ray data, and they don't see anything that corresponds to the plus-3 species). That would appear to leave the idea that they're using arsenate per se as an ingredient in their biochemistry - otherwise, why would they start to grow in its presence? (The Redfield link above takes up this question, wondering if the bacteria are scavenging phosphorus from dead neighbor cells, and points out that the cells may actually still be growing slowly without either added arsenic or phosphate).

Claim 2: the bacteria take up arsenate from the growth medium. To check this, the authors measured intracellular arsenic by ICP mass spec. This was done several ways, and I'll look at the total dry weight values first.

Those arsenic levels were rather variable, but always run high. Looking at the supplementary data, there are some large differences between two batches of bacteria, one from June and one from July. And there's also some variability in the assay itself: the June cells show between 0.114 and 0.624% arsenic (as the assay is repeated), while the July cells show much lower (and tighter) values, between 0.009% and 0.011%. Meanwhile, the corresponding amount of phosphorus is 0.023% to 0.036% in June (As/P of 5 up to 27), and 0.011 to 0.014 in July (As/P of 0.76 to 0.97).

The paper averages these two batches of cells, but it certainly looks like the June bunch were much more robust in their uptake of arsenate. You might look at the July set and think, man, those didn't work out at all, since they actually have more phosphorus than arsenic in them. But the background state should be way lower than that. When you look at the corresponding no-arsenic cell batches, the differences are dramatic in both June and July. The June batch showed at least ten times as much phosphorus in them, and a thousand times less arsenic, and the July run of no-arsenate cells showed (compared to the July arsenic bunch) 60 times as much phosphorus and 1/10th the arsenic. The As/P ratio for both sets hovers around 0.001 to 0.002.

I'll still bet the authors were very disappointed that the July batch didn't come back as dramatic as the June ones. (And I have to give them some credit for including both batches in the paper, and not trying just to make it through with the June-bugs). One big question is what happens when you run the forced-arsenate-growth experiment more times: are the June cells typical, or some sort of weird anomaly? And do they still have both groups growing even now?

One of the points the authors make is that the arsenate-grown cells don't have enough phosphorus to survive. Rosie Redfield doesn't buy this one, and I'll defer to her expertise as a microbiologist. I'd like to hear some more views on this, because it's a potentially important. There are several possibilities - from most exciting to least:

1. The bacteria prefer phosphorus, but are able to take up and incorporate substantial amounts of arsenate, to the point that they can live even below the level of phosphorus needed to normally keep them alive. They probably still need a certain core amount of phosphate, though. This is the position of the paper's authors.

2. The bacteria prefer phosphorus, but are able to take up and incorporate substantial amounts of arsenate. But they still have an amount of phosphate present that would keep them going, so the arsenate must be in "non-critical" biochemical spots - basically, the ones that can stand having it. (This sounds believable, but we still have to explain the growth in the presence of arsenate).

3. The bacteria prefer phosphorus, but are able to take up and incorporate substantial amounts of arsenate. This arsenate, though, is sequestered somehow and is not substituting for phosphate in the organisms' biochemistry. (In this case, you'd wonder why the bacteria are taking up arsenate at all, if they're just having to ditch it. Perhaps they can't pump it out efficiently enough?) And again, we'd have to explain the growth in the presence of arsenate - for a situation like this, you'd think that it would hurt, rather than help, by imposing an extra metabolic burden. I'm assuming here, for the sake of argument, that the whole grows-in-the-presence-of-arsenate story is correct.

Claim 3: the bacteria incorporate arsenate into their DNA as a replacement for phosphate. This is an attempt to distinguish between the possibilities just listed. I think that authors chose the bacterial DNA because DNA has plenty of phosphate, is present in large quantities and can be isolated by known procedures (as opposed to lots of squirrely little phosphorylated small molecules), and would be a dramatic example of arsenate incorporation. These experiments were done by giving the bacteria radiolabeled arsenate, and looking for its distribution.

Rosie Redfield has a number of criticisms of the way the authors isolated the DNA in these experiments, and again, since I'm not a microbiologist, I'll stand back and let that argument take place without getting involved. It's worth noting, though, that most (80%) of the label was in the phenol fraction of the initial extraction, which should have proteins and smaller-molecular-weight stuff in it. Very little showed up in the chloroform fraction (where the lipids would be), and most of the rest (11%) was in the final aqueous layer, where the nucleic acids should accumulate. Of course, if (water-soluble) arsenate was just hanging around, and not being incorporated into biomolecules, the distribution of the label might be pretty similar.

I think a very interesting experiment would be to take non-arsenate-grown GFAJ-1 bacteria, make pellets out of them as was done in this procedure, and then add straight radioactive arsenate to that mixture, in roughly the amounts seen in the arsenate-grown bacteria. How does the label distribute then, as the extractions go on?

Here we come to one of my biggest problems with the paper, after a close reading. When you look at the Supplementary Material, Table S1, you see that the phenol extract (where most of the label was), hardly shows any difference in total arsenic amounts, no matter if the cells were grown high arsenate/no phosphorus or high phosphorus/no arsenate. The first group is just barely higher than the second, and probably within error bars, anyway.

That makes me wonder what's going on - if these cells are taking up arsenate (and especially if they grow on it), why don't we see more of it in the phenol fraction, compared to bacteria that aren't exposed to it at all? Recall that when arsenic was measured by dry weight, there was a real difference. Somewhere there has to be a fraction that shows a shift, and if it's not in the place where 80% of the radiolabel goes, then were could that be?

I think that the authors would like to say "It's in the DNA", but I don't see that data as supporting enough of a change in the arsenic levels. In fact, although they do show some arsenate in purified DNA, the initial DNA/RNA extract from the two groups (high As/no P and no As/high P) shows more arsenic in the bacteria that weren't getting arsenic at all. (These are the top two lines in Table S1 continued, top of page 11 in the Supplementary Information). The arsenate-in-the-DNA conclusion of this paper is, to my mind, absolutely the weakest part of the whole thing.

Conclusion: All in all, I'm very interested in these experiments, but I'm now only partly convinced. So what do the authors need to shore things up? As a chemist, I'm going to ask for more chemical evidence. I'd like to see some mass spec work done on cellular extracts, comparing the high-arsenic and no-arsenic groups. Can we see evidence of arsenate-for-phosphate in the molecular weights? If DNA was good enough to purify with arsenate still on it, how about the proteome? There are a number of ways to look that over by mass-spec techniques, and this really needs to be done.

Can any of the putative arsenate-containing species can be purified by LC? LC/mass spec data would be very strong evidence indeed. I'd recommend that the authors look into this as soon as possible, since this could address biomolecules of all sizes. I would assume that X-ray crystallography data on any of these would be a long shot, but if the LC purification works, it might be possible to get enough to try. It would certainly shut everyone up!

Update: this seems like the backlash day. Nature News has a piece up, which partially quotes from this article Carl Zimmer over at Slate.

Comments (35) + TrackBacks (0) | Category: Biological News | General Scientific News

December 6, 2010

A Quick Glassware Question

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Posted by Derek

Here's a lab equipment question that someone probably knows the answer to, but that someone isn't me. Anyone know where you can buy Corex glass? I'm looking for a tube of the stuff, about 3cm by 28cm, but the only thing I can find are centrifuge tubes. The stuff is (or at least was) made by Corning. It's an aluminosilicate and it's mechanically quite strong, so the centrifuge use makes sense, but no one seems to sell a plain tube of the stuff. Any ideas?

Comments (16) + TrackBacks (0) | Category: Life in the Drug Labs

Exit Kindler

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Posted by Derek

Came the sudden news over the weekend that Jeff Kindler is stepping down as CEO of Pfizer. Actually, it's not so sure that "stepping down" is the right verb phrase to use. No one knew that he was retiring, and the departure of a CEO is usually given a bit more foreshadowing. (It's also usually press-released during the working week, for that matter).

No, this looks sudden. Honestly, though, I'd be surprised if Kindler doesn't feel a sense of relief stealing over him. Pfizer's had a horrendous time of it under him, but a lot of the horrendousness was already in motion when he took over. He's done nothing (given the Wyeth deal) to slow down the horrendous momentum, but Pfizer seems to have decided on its runaway-train corporate model many years ago.

So it's hard to see how changing CEOs is going to affect things much. The company is way too huge, and Lipitor is still going off patent. Even if the new guy (Ian Read) were to have an absolute magic wand effect on research productivity (and research luck), he won't be in the job long enough (ten years? twelve?) to see the effects at the other end of the pipeline. And if he wants to reverse course, to stop trying to acquire-your-way-out-of-trouble, that's going to be very difficult. In fact, given how Pfizer's unloaded various facilities (and people) after these acquisitions, it's going to be like trying to unbake a cake.

I wish Read luck. But I wouldn't run Pfizer, not for what twice they're paying him.

Comments (50) + TrackBacks (0) | Category: Business and Markets

December 3, 2010

Not On My Street - I Hope

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Posted by Derek

Several people have called this guy to my attention: the Escondido wild man who seems to have had a good-sized explosives factory going in his house. He had kilo quantities of (highly explosive) PETN, HMTD, and all kinds of other things you Do Not Want in your basement (see that Chemistry Blog link for a list).

In fact, he and his home chemistry operation seem to have been too much for local law enforcement, who (at least at last report) bailed out of the house and haven't finished searching it yet. That sounds like an excellent decision - you couldn't pay me to go in the place and poke around. On the one hand, perhaps his lab technique wasn't so bad: he was able to work in those quantities without blowing himself up. But on the other hand, and by golly this hand wins, anyone who makes kilos of such things at home has very skewed ideas about risk, to the point that you don't really know what they're capable of. The owner's day job appears to have been robbing banks, which fits right in.

The latest news is a decision that the only way to deal with the house is to burn it. A sixteen-foot fire-resistant wall is being built around the place, and they're just going to let it rip. Beats going around in there opening drawers and looking under the sink, for sure.

Comments (34) + TrackBacks (0) | Category: Chemical News

Going to Let Someone Else Do This One

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Posted by Derek

Fluorinated compounds are always of interest to a medicinal chemist, and difluordioxolanes are perfectly reasonable things to put into a drug's structure. But any method that first uses thiophosgene (you can buy it easily, but here's a good old prep that gets across its fine qualities) and follows that up with bromine trifluoride (which shares many of the wonderful properties of its sibling). . .well, let me know how it goes, and do it far downwind of me.

Comments (14) + TrackBacks (0) | Category: Chemical News

Guess the Author: Revealed

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Posted by Derek

Well, as those of you who searched for the phrases found, the person responsible for the nonsense quoted here is none other than Ray Kurzweil, who with his co-author Terry Grossman published Fantastic Voyage: Live Long Enough to Live Forever in 2004.

Kurzweil is, of course, a widely quoted futurist. He's also an extremely accomplished inventor and a very intelligent man; there's really no doubt about either of those statements. But his techno-optimism, which I broadly share, still leaves me sounding like H. L. Mencken with a head cold. I think that all kinds of wonderful things are possible, and so does Kurzweil - but he thinks that they're not only possible, but that they're happening right now.

I've had occasion to look over Kurzweil's predictions before. What worries me about his futurism is that whenever he starts talking about a field that I know well, he suddenly sounds to me as if he's gone off the rails. And when that happens, well, you have to wonder about the rest of it.

These latest thoughts were prompted by an article by John Rennie, an acidic look at Kurzweil's prediction record in the areas that he should know best (computing, engineering, etc.) His record in medicine is no improvement. And seeing stuff like this alkaline-water nonsense (which I really didn't know he was into) makes me reluctantly mark him even further down. Honestly, if you go for that stuff, you've lowered your defenses against dumpster-loads of hoo-hah. It's very, very hard for me to take seriously anyone who pushes the health benefits of "alkalinized water". But people do.

Comments (18) + TrackBacks (0) | Category: Snake Oil

December 2, 2010

Life With Arsenic: Who'd Have Thought?

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Posted by Derek

Update: a further look at the details of this paper is in a later post.

So: arsenic for phosphorus? That's the big news from NASA today. I listened to much of the press conference, and I've read the paper in Science. Is this real - and if it is, what does it tell us?

Let's do the second part first. Phosphorus is an extremely important element for every living thing on Earth. It's mostly found as phosphate, and phosphate groups are found all over the place: decorating proteins, carbohydrates, and lipids, as the invariable outside of DNA helices, and as the key part of the ultimate energy currency of every living cell, ATP. Phosphate's no bit player.

This is a good time to emphasize that (as far as we can tell) all life on Earth shares the same chemistry and the same kinds of biomolecules. Humans, frogs, fruit flies, fungi, tube worms on the ocean floor, lichens in Antarctica, and weirdo single-celled creatures living in boiling hot springs: we all have cells full of proteins, carbohydrates, lipids, and nucleic acids. We use DNA and RNA to pass on our genetic information, and the enzymes we use to manipulate them and to power our cells are all similar enough that we just have to share a common ancestor. (Either that, or life only gets going in a very specific way indeed).

One thought about today's press conference was that it might be announcing "alien life on Earth". That's been a subject of argument for quite a while. Even though everything we've ever found is of the same family tree, that doesn't rule out (logically or practically) the possibility that some other form of life, with different chemistry entirely, might be hanging out in its own environment. A good deal of searching has failed to turn it up, but (if it's such different stuff) we might be looking for it in the wrong ways, or might even have trouble recognizing it when we see it.

That's not what today's work has turned up, though - but it's probably the next best thing. What this group was looking for were hypothetical organisms that have learned to use arsenic instead of phosphorus. There are environments that are much richer in arsenic (and its corresponding arsenate salts) than they are in phosphorus. And arsenic is right under phosphorus in the periodic table, and forms similar sorts of compounds (albeit with rather different behavior), so. . .maybe it could substitute? Well, they didn't find any native arsenic-users - but they did force some into existence. They took a strain of bacteria from such an environment (Mono Lake sediments) and starved it of phosphate while providing it plenty of arsenate. The colonies that grew under these conditions were picked out and grown under even higher arsenate concentrations, and the process was continued stage after stage.

The end result appears to be bacteria that have incorporated arsenate into their metabolism. They still have phosphate in them, but not enough to keep everything running on a phosphate basis. Some parts have switched over to arsenate, without gumming up the works completely. That surprises me quite a bit - I really wouldn't have thought that things could be pushed that far. After all, in higher organisms, it's that arsenate-for-phosphate switch that's responsible for arsenic's reputation as a poison. Eventually, some key enzyme systems can't handle the switch and cease to function.

But not in these bacteria. They look different and grow more slowly than their phosphate-saturated brethren, and they'd clearly like ditch the arsenic at the first opportunity (add phosphate and they start growing more vigorously). But they're getting by, presumably with just enough phosphate to hold things together. (Have they hit the wall, one wonders?) A number of physical methods all point in the same direction, to arsenate being incorporated into their biomolecules. We still don't know where most of it goes, or how the various phosphate-manipulating enzymes manage to still work, but working out those details will keep a lot of people busy for quite a while. Personally, I'd love to see some X-ray structures of aresenate-containing proteins or nucleic acids, and I'm sure that the people who reported this are trying to get some.

So what does this mean? Well, you can apparently bend the most basic chemistry of life as we know it quite a bit before it breaks. As I said, I really would not have thought that this could be possible - we're all going to have to keep rather more open minds about what biochemical systems can handle. This makes the arsenic-from-the-ground-up idea look a lot more plausible, too, and you can be sure that the search for such organisms (using arsenate naturally, without having to be forced in the lab) will intensify.

It also makes you wonder about what other directions the biochemistry we know of can be stretched. Selenium for sulfur is my best guess - there, you have the advantage that selenium already has a small but real role in biochemistry as it is. I don't know of any environments that are higher in selenium than sulfur, but it would be worth trawling the closest candidates, culturing some bacteria, and giving them the same forcing treatment that was used here. If you really wanted to go wild, you could try pushing down to tellurium and down to antimony in the phosphorus column. Now, I really don't think those have much of a chance, but you never know. It's a lot more plausible to me than it was yesterday.

And the implications for extraterrestrial life are. . .what? Well, we keep finding the sorts of chemicals that we live with (amino acids, simple carbohydrates and the like) out in space. Our type of biochemistry might be fairly common - and if it is, it's good to know that it has a lot of wiggle room in it. It's hard for me to imagine a planet that's loaded down with arsenic and is short of phosphorus, but hey, it's a big universe. Big enough, it appears, for all kinds of weird things. It's great.

Comments (76) + TrackBacks (0) | Category: Life As We (Don't) Know It

Amazing Stuff! Guess Where It's From. . .

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Posted by Derek

OK, let's try a game of "Identify the Author". No fair Googling - that'll call it right up. No, see if you can figure out on your own who believes this:

"Animal cells survive best in an alkaline environment with a blood pH of 7.35 to 7.45. Plant cells are the opposite; they prefer an acidic environment. As our bodies become increasingly acidic, some cells adapt through an internal evolutionary process and become more like plant cells. These abnormal plantlike cells have a high tendency to become cancer cells, which thrive in an acidic environment. So an important strategy for preventing or treating cancer is to maintain an alkaline environment in the body."

No, it's not our old friend Kevin Trudeau, although it sure does sound like him and the other "pH is destiny" people. The guy I'm writing about does indeed sell nutritional supplements, though, and has sold a device to make "alkaline water" at home. About that:

"Another issue concerns the infrastructure of water. Magnetic resonance imaging reveals that most tap water is organized into microclusters of about 12 water molecules each. In alkalinized water, the microclusters are reduced in size to only six molecules per cluster. This enhances the permability, solubility, and absorption of the water, thereby boosting its detoxification effects."

Great stuff! I'll bet you've never seen anything that enhances the solubility of water before. There are a lot of water hucksters out there, for sure, and these claims could be slapped on any of a thousand shady web sites and fit right in.

But that's not where I got them. This guy doesn't have any late-night infomercials, or at least not yet. I'll leave this post up for a while, then update it with the real source, and a few more comments. . .

Update: Here's the source, with more comments.

Comments (53) + TrackBacks (0) | Category: Snake Oil

HIV Therapies: A Thank-You

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Posted by Derek

A rare op-ed note of appreciation for the drug industry: who would have predicted, 20 years ago, that the viral disease for which we have the widest range of effective therapies would be HIV?

Comments (20) + TrackBacks (0) | Category: Infectious Diseases

Ghostwriting On the Larger Scale

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Posted by Derek

You've heard, no doubt, of the problem of ghostwritten articles associated with the drug industry. But now there's a report of an entire ghostwritten book. It is (was, since it came out over ten years ago) a guide for family physicians on psychiatric pharmacotherapy, and its authors - scratch that, I mean the names on the cover - are the current chairman of the psychiatry department at Miami and the former chairman at Stanford.

Now, it's not like these two would have been likely to sit down and write the book themselves under normal conditions, either. Had they been so minded, they would surely have farmed out the work to lesser colleagues. Textbook writing like this is not an exalted activity. But from what this article says, it does look as if a medical writing firm working with SmithKline did the actual grunt work, and that it was the company that had final approval over the page proofs.

I have no idea if the content of the book is accurate or not, but that's really only a secondary point. Signing your name as an author to something written by someone else, for their own interests, is unethical. That's the point.

Comments (6) + TrackBacks (0) | Category: Why Everyone Loves Us

December 1, 2010

Novartis, Meet Novartis (Job Cuts or Not?)

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Posted by Derek

Here we have a Reuters story from November 21: "Novartis Says No Plans to Cut Thousands of Jobs". This was in response to a Swiss newspaper article that said the company was planning something similar to what Roche has done.

And here we have an article from nine days later: "Novartis Plans to Cut 1,400 Drug Sales Jobs in US". To be sure, this isn't, technically, "thousands". And Novartis may well not be thinking along exactly the same lines as the Roche plan. But still.

Comments (20) + TrackBacks (0) | Category: Business and Markets

The Sames-Sezen Case: The Feds Speak

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Posted by Derek

Paul Bracher at Chembark broke the news that the Office of Research Integrity has issued a finding on the Sames-Sezen misconduct case at Columbia. This was big news back in 2006 and 2007, and it should still be news now.

For those who haven't followed this, the case concerns a series of papers published from Dalibor Sames' lab at that university on some interesting C-H activation chemistry. This work was largely performed by a graduate student, Bengü Sezen, but none of it has proven to be reproducible, and there was a string of retractions. (Sezen herself maintained that there were no problems with the work). So far, so bad - but what gives the story more depth is that papers were retracted where Sezen was not even a co-author and the apportionment of blame is still very much arguable. That last point gets into a lot of speculation, but the investigations into the matter haven't done much to clear any of it up.

Here's a PDF with some more background for those wanting to get up to speed, and Paul's earlier posts on the matter have a lot of information for those wanted to dig into this case. I'm not sure that we're ever going to know what really happened here, which is a shame, because we'd all like for it not to happen again.

Comments (24) + TrackBacks (0) | Category: The Dark Side

Resveratrol (SRT501): Development Halted

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Posted by Derek

Back in May, GlaxoSmithKline halted a trial of SRT501, which is a formulation of resveratrol, in myeloma. Now the folks at the Myeloma Beacon site are the first with the news that the company has halted all further development:

According to a GlaxoSmithKline spokesperson, an internal analysis of the kidney failure cases has concluded that they “most likely were due to the underlying disease … However, the formulation of SRT501 was not well tolerated, and side effects of nausea / vomiting / diarrhea may have indirectly led to dehydration, which exacerbated the development of the acute [kidney] failure.”

For this reason, the company decided to halt further development of SRT501 in multiple myeloma. The SRT501 formulation of resveratrol “may only offer minimal efficacy,” explained the Glaxo spokesperson, while increasing the chances of kidney failure. . .

. . .In a separate statement to The Myeloma Beacon, a Glaxo spokesperson explained the rationale for the company’s decision to halt all development of SRT501. Ending all work on SRT501, the spokesperson said, will allow Glaxo to focus its resources on the development of drugs that act similarly to SRT501, but have more favorable properties. The spokesperson mentioned, in particular, SRT2104 and SRT2379 as drugs similar to SRT501 that the company is developing.

These compounds are still a bit of a mystery - they've been in the clinical trial registry for a while, and are certainly the subject of active investigation, but we don't know how they fit into the whole activation-of-SIRT1 brouhaha. They haven't been challenged by the critics of the work, nor specifically defended by GSK, so we're just going to have to see how they perform out there in the real world (which was always going to be the final word, anyway).

But this would appear to be it for resveratrol itself in the real world, as far as GSK's concerned. Hey, does this mean that they'll let their two former Sirtris execs start selling it again on the side, now that they have no interest in the parent compound? One doubts it. But why not?

Comments (27) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials