About this Author
College chemistry, 1983
The 2002 Model
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: firstname.lastname@example.org
December 30, 2010
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!
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December 28, 2010
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.
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December 27, 2010
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!
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December 22, 2010
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. . .
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December 20, 2010
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. . .
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December 17, 2010
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. . .
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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.
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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.
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December 16, 2010
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.
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December 15, 2010
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.
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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)?
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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).
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?
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December 14, 2010
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.
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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. . .
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December 13, 2010
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.
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 a