I'm home today (sick children, etc.), so I'm blogging from next to my daughter's guinea pig cage rather across the hall from my lab. But I have a lab-based question to throw out: what would you say is the chemistry technique or reagent with the worst publication-to-real use ratio?

I have a couple of nominees to get things rolling. For reagent, I would like to advance the montmorillonite clay stuff. I cannot count how many papers I have seen on its use as a Lewis acid, catalyst, and all-around good thing to have, but I have never used it myself, never spoken with anyone who has, and never (to my recollection) heard it suggested as a possible thing to try when someone encountered a synthetic problem. For all I know it's a fine reagent, but its footprint does not seem to be very large. I actually have used benzotriazole, but I've never seen an actual container of montmorillonite K-10.

For general technique, I'm tempted to nominate ionic liquids. Man, are there ever a lot of publications on those things, but again, I've never actually encountered them in actual practice. I have heard second-hand of people trying them, so I guess that counts for something, but it still seems to be disproportionate compared to the avalanche of literature citations for the things. The craze seems to have peaked, but still not a week goes by that I don't see a paper.

Nominations? As with the book recommendation post, I'll assemble things into master lists.

So, according to this report, Merck is scouting out locations for a UK facility. No word if it's supposed to have a research component, but. . .as a correspondent points out, if only there were a large research campus that they could somehow get their hands on, convenient to both Cambridge and London, with all the facilities they might need. . .hmmm. . .

I get regular requests to recommend books on various aspects of medicinal chemistry and drug development. And while I have a few things on my list, I'm sure that I'm missing many more. So I wanted to throw this out to the readership: what do you think are the best places to turn? This way I can be more sure of pointing people in the right directions.

I'm interested in hearing about things in several categories - best introductions and overviews of the field (for people just starting out), as well as the best one-stop references for specific aspects of drug discovery (PK, toxicology, formulations, prodrugs, animal models, patent issues, etc.)

Feel free to add your suggestions in the comments, or e-mail them to me. I'll assemble the highest-recommended volumes into a master list and post that. Just in time for the holidays, y'know. . .

The InVivo Blog has a good article on a controversy in the blood-thinning market. Plavix (clopidogrel) has a very strong share of that, of course, but since Effient (prasugrel) was finally approved, Lilly and Dai-Ichii are looking to take as much of that market as they can. And one opening might be that not everyone responds similarly to Plavix.

In some cases, that's because there are some drug-drug interactions, a problem the FDA has recently addressed. The proton pump inhibitors, especially, are metabolized through the CYP2C19 pathway. That's a problem, since that enzyme is needed to convert clopidogrel into its active form (Plavix, as it comes out of the pill, is a prodrug - its thiophene ring needs to get torn open). This sort of thing has been seen many times before - it's one of the many headaches that you can endure in drug development as you profile the metabolizing pathways for your drug candidate and compare them to the other compounds your patient population might be taking. There are some combinations that just will not work (several involving CYP3A4, which is often the first one you test for), and it looks like we can add Plavix/2C19 to the list.

But the population genetics of the 2C19 enzyme are rather heterogeneous. About a third of the patients taking Plavix have a less-active form of the enzyme to start with, and they might not respond as robustly to the drug. The FDA has emphasized this effect in its latest public health warning. That's an opportunity for Effient, since it doesn't go through that metabolic route.

The In Vivo people point out, though, that this story isn't being driven by the usual players. It's not the FDA that's pushed to find this out, and it's not even Eli Lilly. It's Medco and Aetna. They studied their insurance claims data to see if the numbers supported the proton pump inhibitor/Plavix interaction, found that they did, and publicized their findings - and that led to an actual observational trial from BMS and Sanofi, which confirmed the problem. Now Medco is going further, and is actually running its own observational study comparing Plavix and Effient. Their theory is that the efficacy that Lilly showed compared to Plavix was driven by the (deliberate, one assumes) inclusion of a high number of poor metabolizers.

Medco is getting ready for generic Plavix, and trying to keep its costs down by making the case that the drug will do the job just fine for most patients. They could, on the other hand, end up making the case for Effient in that poor-metabolizing third of the patients, which would also be interesting. Lilly would presumably settle for that, although they'd like even more of the market if they can get it, naturally.

And I have to say: I like this sort of thing. I like it a lot. This, to me, is how the system should work. Companies are pursuing their own competing interests, but in the end, we get a higher standard of care by finding out which drug really works for which patients. The motivation to do all this? Money, of course, earning it and saving it. This may sound crass, but I think that's a reliable, proven method to motivate people and companies, one that works even better than depending on their best impulses. You could even build an economic system around such effects, with some attention to channeling these impulses in ways that benefit the greatest number of people. Worth a try.

Two more blogs that I've forgotten to add are now on the blogroll: Pharma Conduct and Chemical Space. Welcome!

Update: oh yeah, Pharmalot returns, too!

I was going over some thermodynamics the other day, and it hit me that this was just the sort of thing I always tried to avoid when I was actually taking chemistry courses in college and grad school. And here I was, looking it up voluntarily and even reading it with some pleasure. A couple of professors of mine would have been rather pleasantly surprised at the sight, though, since physical chemistry (especially) tended to exacerbate my often lazy approach to my course work.

When I look back on it, it's a very good thing that my graduate school curriculum only featured classes during the first year. Because I was trying to get away with more and more by doing less and less, and those two trend lines were heading toward an intersection. (Another example of that from my grad-school past can be found here). In the end, the chrome-plated jaws of destiny did not quite snap shut on my academic career, but it was a near thing. I can well recall being assigned problem sets in a course during my first year of grad school, with a strong probability of having to be called up to the board to work out a random one from the list in front of the professor and the class, and just not getting around to doing them.

So more than once, I'd be called upon to present a problem I hadn't actually bothered to look at. A classmate of mine, Bill, had a similar approach to his work, and he and I would sometimes end up side by side at the board, quietly saying things to each other like "You do any of these?" "Nope, me neither. This one look like the Eyring equation to you?" At the same time, I was ceasing to take notes in the class, finding that (for whatever reason) I wasn't getting much out of the lectures, and seemed to be doing OK by reading the material.

The professor involved noticed me sitting there without a notebook day after day, and called me in for a chat. "You seem to have ceased bringing any sort of writing implement to my lectures", he said. "I presume that there's some reason for that?" I stammered out some line about how I found that I was able to concentrate more on the material when I wasn't having to worry about getting it down on paper, and I could tell that he didn't buy that one for a minute. "I see. . ." he said slowly, and let me go. The next lecture (and you knew this sentence would start out that way), he was up at the board talking about More O'Ferrall plots or something of the sort, and in the middle of explaining one said ". . .then when you move into this quadrant the transition state is affected like so and does that look OK to you, Derek?"

Zzzzzip! Some home-security monitor circuit in my brain tripped, and I returned to reality with the unpleasant sensation of having been dropped into my seat from a helicopter. "Umm. . .no mistakes that I can see", I said, which was certainly true, and the professor gave me a narrow-eyed look. "Yes. . .no doubt".

So no, this couldn't have gone on in that style for too much longer, and it was with relief that I moved on to full-time lab work. But I still have little patience for lectures I find uninteresting. I'm just glad that no one's passing out exams afterwards. . .

There's a new paper out in Nature that presents an intriguing way to look for off-target effects of drug candidates. The authors (a large multi-center team) looked at a large number of known drugs (or well-characterized clinical candidates) and their activity profiles. They then characterized the protein targets by the similarities of the molecules that were known to bind to them.

That gave a large number of possible combinations - nearly a million, actually, and in most cases, no correlations showed up. But in about 7,000 examples, a drug matched some other ligand set to an interesting degree. On closer inspection, some of these off-target effects turned out to be already known (but had not been picked up during their initial searching using the MDDR database). Many others turned out to be trivial variations on other known structures.

But what was left over was a set of 3,832 predictions of meaningful off-target binding events. The authors took 184 of these out to review them carefully and see how well they held up. 42 of these turned out to be already confirmed in the primary literature, although not reported in any of the databases they'd used to construct the system - that result alone is enough to make one think that they might be on the right track here.

Of the remaining 142 correlations, 30 were experimentally feasible to check directly. Of these, 23 came back with inhibition constants less than 15 micromolar - not incredibly potent, but something to think about, and a lot better hit rate than one would expect by chance. Some of the hits were quite striking - for example, an old alpha-blocker, indoramin, showed a strong association for dopamine receptors, and turned out to be an 18 nM ligand for D4, which is better than it does on the alpha receptors themselves. In general, they uncovered a lot of new GPCR activities for older CNS drugs, which doesn't surprise me, given the polypharmacy that's often seen in that area.

But they found four examples of compounds that jumped into completely new target categories. Rescriptor (delavirdine), a reverse transcriptase inhibitor used against HIV, showed a strong score against histamine subtypes, and turned out to bind H4 at about five micromolar. That may not sound like much, but the drug's blood levels make that a realistic level to think about, and its side effects include a skin rash that's just what you might expect from such off-target binding.

There are some limitations. To their credit, the authors mention in detail a number of false positives that their method generated - equally compelling predictions of activities that just aren't there. This doesn't surprise me much - compounds can look quite similar to existing classes and not share their activity. I'm actually a bit surprised that their methods works as well as it does, and look forward to seeing refined versions of it.

To my mind, this would be an effort well worth some collaborative support by all the large drug companies. A better off-target prediction tool would be worth a great deal to the whole industry, and we might be able to provide a lot more useful data to refine the models used. Anyone want to step up?

Update: be sure to check out the comments section for other examples in this field, and a lively debate about which methods might work best. . .

I've gone through the blogroll, clearing out inactive sites and adding new ones. So welcome to Med-Chemist, Chemical Crystallinity,
Synthetic Nature, , Chiral Jones, and P212121!

And I've also added another category for chemistry and pharma database sites. There you'll find a quick way to access the copious piles of information from Drugbank, Emolecules, ChemSpider, PubChem, DailyMed, Druglib, and Clinicaltrials.gov.

As always, if I've left a blog (or your blog!) off the list, drop me an e-mail and let me know about it. If it's of potential interest to the readership here, on it goes.

I've been remiss in not mentioning this, but I just found out recently that Warren DeLano (the man behind the excellent open-source PyMOL program) passed away suddenly earlier this month. He was 37 - another unfortunate loss of a scientist who had done a lot of fine work and was clearly on the way to doing much more.

I notice that as I write this I have a PyMOL window open on my desktop; I use the program regularly to look at protein structures. Si monumentum requiris, circumspice.

Over the weekend, the results in a small cardiovascular trial came out that compared Merck's Zetia (ezetimibe/simvastatin) (correction - ezetimibe alone) against Abbott's Niaspan (time-release niacin). Niacin's an underappreciated therapy in the field - it has tolerability problems, mainly irritating and uncomfortable hot flushing, but it really does seem to help normalize lipid numbers. (And that's why Merck itself, among others, have taken cracks at the market).

This latest trial was a small one, but people have been starved for data on Zetia ever since it took a surprising hit (in the ENHANCE trial) suggesting that it might not be very efficacious. There's an ongoing larger trial that should answer this question once and for all, but those numbers won't be showing up for another two years. For now, anything that can help clarify what's going on is of great interest to Merck, its investors, and to cardiologists and their patients.

And Matthew Herper at Forbes is right: these latest numbers are disastrous. The study (funded by Abbott) isn't the greatest piece of clinical research in the world - it didn't study nearly as many patients as it was designed to, since it was halted early. (Here it is in the NEJM). But it still shows Niaspan as clearly superior to Zetia, and it makes a person wonder if taking Zetia is basically an expensive way to take a possibly-inadequate dose of simvastatin. In a way, the relatively small size of the study actually helps it a bit - getting numbers that definitive without having to go to much larger sample sizes isn't so easy in cardiovascular trials, so the feeling is that there much be something here.

As Herper's article details, Merck is trying to spin this as a big win for their competition, not a big loss for their own drug. But that comes close to being logically impossible: cholesterol lowering, like many other therapeutic areas, is nearly a zero-sum game. If patients take Niaspan (or any other competing drug), they're not going to be taking Zetia. This one was certainly a victory for Abbott (and generic niacin, for those who can take it), but it was a loss for Merck as well.

The FDA's not coming out of all this looking very good, either:

"How is it possible for a drug to have $4 billion in sales without any evidence of benefit?" says Harlan Krumholz, a cardiologist at Yale University. He said that the small size of the two imaging studies mean they couldn't render a clear verdict on Zetia. "But they don't instill any confidence in it either. " Douglas Weaver, head of cardiology at the Henry Ford Hospital in Detroit says: "We've used Zetia without sufficient amounts of clinical data to support it. Using it may be right, it may be wrong, but we don't know right now."

But it's worth remembering that Zetia's mode of action made perfect sense, and that it really does lower cholesterol to what you'd think would be a very beneficial degree. But it probably has several other effects beyond simple LDL lowering, and just looking at that number is clearly (in hindsight) not enough of a clinical surrogate marker. As the study authors put it:

If viewed properly, this hypothesis-generating finding is not an indictment of the overall importance of reducing LDL cholesterol for the purpose of preventing cardiovascular events, as illustrated by therapies based on statins or nonstatins (e.g., bile acid sequestrants). Rather, this adverse relationship may be attributable to the net effect of ezetimibe, a drug with diverse actions, not all of which are measured through its effects on intestinal cholesterol absorption and LDL cholesterol level. Taken together with a preexisting concern regarding the clinical effectiveness of ezetimibe, our findings challenge the usefulness of LDL cholesterol reduction as a guaranteed surrogate of clinical efficacy, particularly reduction achieved through the use of novel clinical compounds.

But as I recall, statins themselves were first approved based largely on lowered LDL, with better outcome data only showing up later. In that case, the surrogate marker paid off, but not this time. What all this is telling us, then, is that we don't know nearly as much about cholesterol and cardiology as we thought we did. And if we don't understand that area well enough, after all these years and all this effort, what parts of medicine do we really understand?

As many readers may have heard by now, Keith Fagnou of the University of Ottawa has suddenly died from what appears to be H1N1 influenza.

I'm awaiting confirmation of that diagnosis, which is worrisome for all sorts of other reasons, but whatever the cause, this is a loss for synthetic chemisty. Prof. Fagnou had published many interesting and useful papers on catalysis of bond-forming reactions, an area that's been growing steadily in importance for years and shows no signs of faltering. We need all the smart, capable people we can get working on such things, and I'm very sorry that we've lost one. Condolences to his family, colleagues, and friends.

When we screen zillions of compounds from our files against a new drug target, what can we expect? How many hits will we get, and what percentage of those are actually worth looking at in more detail?

These are long-running questions, but over the last twenty years some lessons have been learned. A new paper in J. Med. Chem. emphasizes one of the biggest ones: if at all possible, run your assays with some sort of detergent in them.

Why would you do a thing like that? Compound aggregation. The last few years have seen a rapidly growing appreciation of this problem. Many small molecules will, under some conditions, clump together in solution and make a new species that has little or nothing to do with their individual members. These new aggregates can bind to protein surfaces, mess up fluorescent readouts, cause the target protein to stick to their surfaces instead, and cause all kinds of trouble. Adding detergent to the assay system cuts this down a great deal, and any compound that's a hit without detergent but loses activity with it should be viewed with strong suspicion.

The authors of this paper (from the NIH's Chemical Genomics Center and Brian Shoichet's lab at UCSF) were screening against the cysteine protease cruzain, a target for Chagas disease. They ran their whole library of compounds through under both detergent-free and detergent conditions and compared the results. In an earlier screening effort of this sort against beta-lactamase, nearly 95% of the hits (many of them rather weak) turned out to be aggregator compounds. This campaign showed similar numbers.

There were 15 times as many apparent hits in the detergent-free assay, for one thing. Some of these were apparently activating the enzyme, which is always a bit of an odd thing to explain, since inhibiting enzyme activity is a lot more likely. These activators almost completely disappeared under the detergent conditions, though. And even looking just at the inhibitors, 90% of the hit set in the detergent-free assay went away when detergent was added. (I should note that control cruzain inhibitors performed fine under both sets of assays, so it's not like the detergent itself was messing with the enzyme to any significant degree).

They point out another benefit to the detergent assay - it seems to improve the data by keeping the enzyme from sticking to the walls of the plastic tubes. That's a real problem which can kick your data around all over the place - I've encountered it myself, and heard a few horror stories over the years. But it's not something that's well appreciated outside of the people who set up assays for a living (and not always even among some of them).

So, let's get rid of those nasty aggegators, right? Not so fast. It turns out that some of the compounds that showed this problem during the earlier beta-lactamase work didn't cause a problem here, and vice versa. Even using different assays designed to detect aggregation alone gave varying results among sets of compounds. It appears that aggregation is quite sensitive to the specific assay conditions you're using, so trying to assemble a blacklist of aggregators is probably not going to work. You have to check things every time.

One other interesting point from this paper (and the previous one): curators of large screening collections spend a lot of time weeding out reactive compounds. They don't want things that will come in and react nonspecifically with labile groups on the target proteins, and that seems like a reasonable thing to do. But in these screens, the compounds with "hot" functional groups didn't have a particularly high hit rate. You'd expect a cysteine protease to be especially sensitive to this sort of thing, with that reactive thiol right in the active site, but not so. This ties in with the work from Benjamin Cravatt's group at Scripps, suggesting that even fairly reactive groups have a lot of constraints on them - they have to line up just right to form a covalent bond, and that just doesn't happen that often.

So perhaps we've all been worrying too much about reactive compounds, and not enough about the innocent-looking ones that clump up while we're not looking. Detergent is your friend!

There's a disturbing article out at the New England Journal of Medicine on studies conducted on Neurontin (gabapentin) for various unapproved indications. Parke-Davis (and later Pfizer) looked at a wide range of possible indications for the drug - migraine, neuropathic pain, bipolar disorder, and more. That in itself isn't unusual, since CNS drugs often have rather broad and poorly defined mechanisms, and it's not like we understand any of them all that well.

What is unusual is the pattern found when comparing the internal reports with the published versions that showed up in the literature. The authors found that:

"More than half the clinical trials that we included in our analysis (11 of 20) were not published as full-length research articles. For 7 of the 9 trials that were published as full-length research articles, a statistically significant primary outcome was reported, and for more than half these trials, the outcome specified in the published report differed from the outcome originally described in the protocol. Three of the four trials with an unchanged primary outcome had statistically significant results for the protocol-specified primary outcome. Secondary outcomes also frequently differed between the protocol and the published report. Thus, trials with findings that were not statistically significant (P≥0.05) for the protocol-defined primary outcome, according to the internal documents, either were not published in full or were published with a changed primary outcome. . .all the changes that took place between what was specified in the protocol, what was known before publication (as presented in the internal company research reports), and what was reported to the public led to a more favorable presentation in the medical literature. . ."

The authors go on to point out that changing a primary outcome after you see the data is, in fact, a statistical sin (although that's not quite the phrase they use!) You really can't go around doing that, because you can end up chasing after random chance (and avoiding that is the whole point of running well-controlled trials). This does not cover Pfizer and Parke-Davis with glory, but it's worth noting that there's plenty of blame to go around when it comes to this practice:

"Our study is based on a relatively small number of trials undertaken to test a single drug manufactured by a single company and its successors. Furthermore, if a major purpose of the studies we examined was to promote off-label uses of gabapentin, the selective reporting we observed could be more extreme than that observed for studies conducted for other reasons. Previous studies in different settings have shown evidence of these same biases, however. Indeed, selective outcome reporting does not appear to be limited to studies funded by drug companies. Chan and colleagues examined published trials funded by the Canadian Institutes of Health Research and found that 40% of stated primary outcomes differed between the protocol and the published report. In addition, we cannot be certain that selective reporting was a decision made by employees of Pfizer and Parke-Davis, since the authors of the published reports included nonemployees. We did not systematically assess the methodologic quality of the included trials as described in the publications we examined. Previous research has indicated that quality scores are higher for trials conducted by the pharmaceutical industry than for trials conducted by not-for-profit entities, although reports from industry-sponsored trials have potentially distorted the scientific record because of other, less easily measured study factors."

That doesn't get the folks who conducted these gabapentin studies off the hook, although I should note that Pfizer disputes the conclusions of this article (as you'd certainly think that they would). And it's also worth noting that some of its authors have done work for the plaintiffs in suits against Pfizer over gabapentin (thus all the familiarity with the internal company documents, which came to light during discovery proceedings). But again, I don't see how that negates the paper's conclusions, and if Pfizer has any hard data that would do so, I think they should produce it with all speed.

And no, it's just a coincidence that this post involve Pfizer, after I've been going on about their merger business all week. Unfortunately, I think that they're probably not the only company that could be pointed at. But we in the industry shouldn't have things like this for others to uncover in the first place. Should we?

Or perhaps one should wait until spring - it's the wrong season for high-nitrogen mixtures to be applied:

Speaking at the Reuters Health Summit on Wednesday, Kindler said Pfizer has melded and reshaped its research and development facilities within 20 days of buying Wyeth on October 15. With previous huge mergers, he said, that process had taken "literally years."

. . .Swift reorganization of the two companies' research operations stands in contrast to "the distractions, the disruptions and the delays that have plagued mergers of our company and others in the past," Kindler said.

With the waves of layoffs going on, and all the nasty structural changes we're seeing in this business, it's easy to start feeling a toxic combination of fear and despair. And while I understand that, I'm going to try to briefly argue against it.

(1) I think that, in the years to come, that people are most definitely going to need medicines. And by that, I mean new ones, because there are a lot of conditions out there that we can't treat very well. As the world gets (on the average) older and wealthier, this need will do nothing but increase. In many cases, pharmaceutical treatment is cheaper than waiting and having surgery or the like, so there's a large scale cost-saving aspect to this, too.

(2) I also think that many of these medicines are still going to be small molecules. Now, biological products can be very powerful, and can do things that we can't (as yet) do with small molecules - mind you, the reverse is true, too. And I think that biologics will gradually increase their share of the pharma world as we find out more about how to make and administer them. But it is very hard to beat an orally administered small molecule for convenience, cost, and patient compliance, and those are three very big factors.

(3) What we're witnessing now is a huge argument about how we're going to make those small molecule drugs, where we're going to make them, and who will do all those things. And it's driven by money, naturally. We don't have enough new products on the market, which means that we have to sell the ones we have like crazy (which leads to all sorts of other problems, legal and otherwise). At the same time, we're having to spend more and more money to try to get what drugs we can through the whole process. These trends appear unsustainable, especially when running at the same time.

(4) But as Herbert Stein used to say, if something can't go on, then it won't. Right now, the only way out that companies can see is to cut costs as hard as possible (and market as hard as possible). Those both bring in short-term results that you can point at. Long-term, well. . .probably not so good. But in that same long term, we're going to have to find better ways of discovering and developing drugs. If we can improve that process, the fix can come from that direction rather than from the budget-cutting one.

(5) And those improvements don't have to be incredible to make a big difference. We have a 90% failure rate in the clinic as it stands. If we could just work it to where we only lose 8 out of 10 drug candidates, that would double the number of new drugs coming to the market, which would cheer everyone up immensely.

(6) The questions are: can we improve R&D in time? Can we improve it with the resources we have? I think that the demand (and thus the potential rewards) is too great for a solution not to be found, if there's one out there. And we still know so little about what we do that I can't imagine that answers aren't out there somewhere. Who's going to find them? How long will it take? Where are they? I've no clue. But that looks like the way out to me.

In an attempt to get the story out to a wider audience, I have a piece up at The Atlantic's Business site on the Pfizer layoffs, the J&J layoffs, and what's happening to the traditional expectations for the way research is done. This is going to be a long process, though, and I keep wondering if we're still just in the early parts of it. . .

A reader who's (unfortunately) in a position to know the details sends along some numbers on Pfizer's chemistry shakeout. According to his figures, Pfizer (pre-Wyeth merger) had about 900 chemists. The Wyeth deal brought in about 350, but no one expected the merged department to stay at 1250 - instead, the guess was that the new chemistry staff would be in the 1000 range, which is what I would have guessed, too.

But the chemistry head count is now apparently headed to about 850: smaller than it was before the merger. I have to assume that outsourced chemistry isn't included in this total, and that that's where the deficit is being made up. It is being made up, right? Pfizer isn't actually trying to become a bigger company with a smaller research staff - right? Posters and coffee mugs about working smarter and doing more with less can only take you so far, you know.

As I say, these are numbers from the inside, and I'll be glad to listen to (and post) corrections to them. But from what I'm hearing, this is accurate - and no one (especially at Wyeth) saw this coming on as hard as it has. . .

I mentioned the H-Cube hydrogenation machine here a couple of years ago as an early example of a commercial flow chemistry machine. As some readers may have guessed, my recent post on hydrogenations was partly inspired by a recent run of activity on this instrument, which came in quite handy.

Until the last couple of days, that is. Now there's a problem, and I'd be glad to hear from any H-Cube users who might know how to solve it. (If you haven't used one, you can probably bail out right now!) What's going on is: when I try to run a hydrogenation in "Full H2" mode, everything works fine until the H2 valve closes. The pump's fine, the flow through the instrument is fine. . .until the status switches to "Running". At that point the flow stops momentarily, then a gout of solvent runs from the outlet all at once, and then. . .nothing. Well, nothing except hydrogen gas - if I dip the outlet tube below the surface of some solvent, I can see that it's still producing that. But there's no flow. Lifting the solvent inlet from the reservoir, I can see that nothing's being taken up - an air bubble forms at the inlet, and just moves up and down.

So there's something going on when the system starts letting hydrogen into the flow, but I'm not sure what that might be. I can always call in the $250/hr folks, but I thought that throwing my problems out onto the blog was at least worth a try. Just to take care of some obvious fixes, so far I've cleaned the metal frit, replaced the Teflon membrane, sonicated the check valve, and tried changing catalyst cartridges. Anyone got any clues after that?

Pharmaconduct.org has another look at Pfizer's announcement yesterday, and tries to address some of the many unanswered questions left open by the company's press release. One thing that struck me (and many others) is that the company talked about "moving a number of functions" from sites like St. Louis and Collegeville, but did not come right out and say that they were closing. I understand that there's more than R&D that goes on in these places, but it still seems as if these moves will leave a lot of empty hallways, which you wouldn't think is the optimum solution.

A topic of local discussion has been the two Cambridge sites the new company has, and you can argue that one either way, too. "They do different things, and both of them should stay" goes up against "Why would you have two research sites in the same town if you didn't need to?" Yesterday's release was silent on this question, too.

Eric at Pharmaconduct has gone so far as to put together a database of Pfizer's moves over the last few years, in an attempt to figure out what they're up to. I wish him luck, and I'll follow the success of this effort with interest. I'm not sure if the company's behavior is subject to this kind of field-zoologist approach, but perhaps it is. At any rate, people with information to contribute can help him find out.

The company has issued a press release detailed which sites are staying, and which are leaving:

Pfizer will have five main research sites that will serve as central hubs for research activities in BioTherapeutics, PharmaTherapeutics and Vaccines. These sites are: Cambridge, Mass.; Groton, Conn.; Pearl River, N.Y.; La Jolla, Calif.; and Sandwich, U.K. These research-oriented laboratories will be supplemented by specialized research capabilities, such as monoclonal antibody discovery in San Francisco, regenerative medicine work in Cambridge, U.K., and research and development activities in Shanghai, China. . .

. . .As part of the consolidation of research sites, Pfizer will significantly reduce R&D activities at some of its sites. The company will move a number of functions from Collegeville, Pa.; Pearl River, N.Y.; and St. Louis to other locations and will discontinue R&D operations in Princeton, N.J.; Chazy, Rouses Point and Plattsburgh, N.Y.; Sanford and Research Triangle Park, N.C.; and Gosport, Slough/Taplow, U.K. In addition, Pfizer will consolidate R&D functions from its New London, Conn., site to its nearby research facility in Groton, Conn.

What we don't know (yet) is how many people will be let go from these sites, and how many will be offered a moving package. Of course, last time around, some people moved and were let go in yet another round, but the future is unwritten. . .more on this as more details emerge.

The latest issue of Nature Medicine has several short articles on patent issues, and is well worth a look if that's your sort of thing. I enjoyed this from the issue's lead editorial:

"An informal poll we conducted while preparing the focus on patents appearing in this issue (pp 1239–1243) disclosed that about two-thirds of scientists, particularly in Europe, don't know who owns the intellectual rights to the discoveries made in their labs. A similarly high proportion don't know if there are any provisions in their job contracts assigning them any rights over their discovery. And roughly half don't even know whether they are legally entitled to open a company based on their research."

As the piece goes on to explain, these turn out not to be particularly hard questions to answer. They are, in fact, answered in just the way you think they are, which makes me wonder a bit about the people who don't know these things. Let's see, even though you're not a lawyer, and don't know much about these things, and you're signing an agreement with a large entity that's very interested in this subject and can afford to pay for good legal advice about it. . .hmm, I wonder who could possibly have the advantage here?

There's a long, detailed article up over at Bloomberg on the recent run of huge fines for off-label promotion of drugs. Pfizer, Lilly, Bristol-Meyers Squibb, and Schering-Plough all get mentioned in great detail.

And there's a key point from the whole depressing thing: the reason that marketing departments do this kind of thing is that it makes money. Even after you pay a billion dollars in fines, you can still come out ahead, and you might not even have to pay the fines. It's just being put down as a cost of doing business - it's a speeding ticket, and it's being weighed against the cost of driving under the legal limit.

But there's no way that our industry will gain - or regain - respect as long as we operate this way. Have the people involved priced that out as well?

So what are we up to now, Day Three of Greater Merck? The merger with Schering-Plough went through earlier this week, and you won't get any more numbers by searching the stock tickers for SGP.

I find that weird, since I started my career there in the late 1980s/early 1990s. But while I was there, it seemed like there were mergers and rumors of mergers every few weeks. That's no doubt a hindsight-enhanced picture I have, but it's safe to say that I heard about S-P merging (or being purchased by) every single major player in the business during my years there. And it didn't happen (not then, at any rate).

My favorite moment came in about 1992 when a colleague came to my office one afternoon saying "It's us and Upjohn. Announced after the close of business on Friday. All of CNS is going to Kalamazoo". I hardly even looked up, uttering a one-word reply that compared this news flash to bovine waste.

"Why do you say that?", he replied. "You don't think it could happen?" "Of course I thing it could happen", I said. "But I'll bet against any specific prediction of when and who. Got any money on you?" "Why don't you think this is the real thing?" he asked again, to which I replied "Because I don't think that any deal this size, set to be announced on Friday, could be so screwed up that you and I would know about it on Tuesday afternoon".

"Well, I kind of see your point there. . .", he began. And of course that particular deal never happened. But I'm sure that there were others that nearly did. That's one of the things that goes on in the background of this industry - there are a lot of tentative discussions and what-if ideas that get looked at briefly (or sometimes not so briefly) which people outside of upper management never hear about. This stuff generally starts to leak (if it does) once it gets closer to really happening, and for every one that happens, there are several that get thought about but never quite work.

Of course, I'm using "work" in the sense of "get completed", not in the sense of "works out in the long run to the benefit of everyone involved". I'm not convinced that many drug company mergers fall into that latter category at all, and that goes for the Merck/Schering-Plough one, too. There don't seem to be any dramatic announcements coming out of the deal so far, and that probably means that the changes (which are, and have to be, coming) will just be delayed while the company takes stock of what it now has, and what it now is.

But, as someone from another company was saying to me last night, the bigger you are, the harder it is to do that. It takes longer before you feel that there's enough information to make a good decision, which is probably why Pfizer's current rearrangements are taking so agonizingly long to make themselves clear. That same decision-making extends, I think, to drug discovery and development issues, which is one reason I don't like the whole mega-company idea to start with.

There's also the groupthink problem. Pfizer, for example, was able to convince itself that inhaled insulin was going to be a big winner, even as people outside the company wondered if that could be quite right. (And not only was it not a big seller, it was an unprecedented disaster). I don't believe that people get any smarter in large groups. Quite the contrary. All that "wisdom of crowds" stuff, as I understand it, is about consulting large numbers of individual thinkers, not getting them all into one room and having them agree on something. Especially if some of the people in the room can decide the salaries and promotions of the rest of the crowd.

I wish both the Merck people and the Schering-Plough people well, and the combined company good fortune, and that's not just because I find myself a stockholder of it. But I wish it hadn't come to this, and I wish it wouldn't keep coming to this, either.

Resveratrol's a mighty interesting compound. It seems to extend lifespan in yeast and various lower organisms, and has a wide range of effects in mice. Famously, GlaxoSmithKline has expensively bought out Sirtris, a company whose entire research program started with resveratrol and similar compound that modulate the SIRT1 pathway.

But does it really do that? The picture just got even more complicated. A group at Amgen has published a paper saying that when you look closely, resveratrol doesn't directly affect SIRT1 at all. Interestingly, this conclusion has been reached before (by a group at the University of Washington), and both teams conclude that the problem is the fluorescent peptide substrate commonly used in sirtuin assays. With the fluorescent group attached, everything looks fine - but when you go to the extra trouble of reading things out without the fluorescent tag, you find that resveratrol doesn't seem to make SIRT1 do anything to what are supposed to be its natural substrates.

"The claim of resvertraol being a SIRT1 activator is likely to be an experimental artifact of the SIRT1 assay that employs the Fluor de Lys-SIRT1 peptide as a substrate. However, the beneficial metabolic effects of resveratrol have been clearly demonstrated in diabetic animal models. Our data do not support the notion that these metabolic effects are mediated by direct SIRT1 activation. Rather, they could be mediated by other mechanisms. . ."

They suggest activation of AMPK (an important regulatory kinase that's tied in with SIRT1) as one such mechanism, but admit that they have no idea how resveratrol might activate it. Does that process still require SIRT1 at all? Who knows? One thing I think I do know is that this has something to do with this Amgen paper from 2008 on new high-throughput assays for sirtuin enzymes.

One wonders what assay formats Sirtris has been using to evaluate their new compounds, and one also wonders what they make of all this now at GSK. Does one not? We can be sure, though, that there are plenty of important things that we don't know yet about sirtuins and the compounds that affect them. It's going to be quite a ride as we find them out, too.

You're supposed to disclose conflicts of interest if you're the author of a scientific paper. For the most part, everyone does, but it's those times that the system breaks down that cause all the trouble. Does this author actually earn a side income from Company X? Is that author actually about to start a new company based on the discovery that's being reported so breathlessly? And does this other author have a big stock position in company Y, whose price will be affected by this new paper? Journal editors want to know about these things, as do readers.

But how far do we go with this idea? An editorial in BioCentury (free PDF version) takes up arms against a new rule for non-financial disclosures from the International Committee of Medical Journal Editors. It requires authors to "report any personal, professional, political, institutional, religious, or other associations that a reasonable reader would want to know about in relation to the submitted work". And it's the inclusion of the words "personal", "political", and "religious" that could cause trouble.

Or maybe it's the inclusion of the word "reasonable". That's a common legal-argument adjective, but on the whole, people are not reasonable when it comes to their political or religious beliefs. (You may have noticed that there's been a debate for several centuries now about whether religious belief has anything to do with reason at all, but I think we'll try to stay out of that one). A dedicated atheist may consider it quite reasonable to want, say, any biological publication featuring Francis Collins of NIH to always feature a statement that Collins is a born-again Christian with a strong interest in reconciling his beliefs with scientific practice. An evangelical Christian reader, on the other hand, may want to have the biology papers flagged for the authors who do not see the hand of a Creator in their field of study. Which of these is "reasonable", if either?

The situation doesn't get any easier when you move towards politics. Do we really want to start listing party affiliations or the like? I realize that the journal editors have no intention of doing any such thing, but no one ever intends for the worms to get so far out of the can, either. When a really contentious issue comes up (such as global warming), plenty of reasonable readers (or perhaps I mean readers who are otherwise reasonable!) would want to see the complete political disclosure done on the authors of every paper, the better to sniff out Error, Self-Interest, and Collusion from either side of the debate.

How are we going to draw these particular lines, and how are we going to draw them in any kind of consistent fashion? Consistency is going to be very hard to achieve. The BioCentury piece points out a recent major disclosure glitch by the editors of the New England Journal of Medicine, and if we go into the full empty-out-your-pockets mode, I worry that the arguments may never cease.

And I've even made it to the last paragraph without mentioning the libertarian none-of-your-business objections to the whole idea. Your thoughts?

Johnson & Johnson says that it could be cutting up to 8,000 jobs. This has been in the wind for a while, but I haven't had any reports yet of what it's doing on the ground to the research sites. Any news from the readers affected, or is that yet to come?

Back in late September I wrote about a controversial paper in the Proceedings of the National Academy of Sciences. It attracted comment for its way-out-there hypothesis: that caterpillars and other larvae arose through a spectacular interspecies gene transfer rather than through conventional evolutionary processes. And it may have been the last paper to make it into the journal by the now-eliminated "Track III" route, which allowed members to essentially cherry-pick their own reviewers. This paper may well have hastened the disappearance of that system, actually - it created quite an uproar.

At the time, I wrote that the paper's hypothesis seemed very likely to be wrong, but at least the author had proposed some means to test it. Now in the latest PNAS come a letter and a full article on the subject. Both mention the testability of the original paper, and go on to point out that such tests have already been done. The paper is written in a tone of exasperation:

Williamson suggested that "many corollaries of my hypothesis are testable." We agree and note that most of the tests have already been carried out, the results of which are readily available in the recent literature and online databases. Here, we set aside (i) the complete absence of evidence offered by Williamson in support of his hypothesis, (ii) his apparent determination to ignore the enormous errors in current understanding of inheritance, gene expression, cell fate specification, morphogenesis, and other phenomena that are implied by his hypothesis, and (iii) the abundant empirical evidence for the evolution and loss of larval forms by natural selection. Instead, we focus on Williamson's molecular genetic predictions concerning genome size and content in insects, velvet worms, and several marine taxa, and we point out the readily available data that show those predictions to be easily rejected.

And you know, they really should set aside those first three points. Entertaining as it is to read this sort of thing, the real way to demolish a paper like Williamson's is to rip it up scientifically, rather than hurl insults at it (however well-justified they might be). There seems to be plenty of room to work in. For example, Williamson predicts that a class of parasitic barnacle will be found to not be barnacles at all, and to have an abnormally large genome, with material from three different sorts of organisms. Actually, though, these organisms have smaller genomes than usual, and from their genes they appear to be perfectly reasonable relatives of other barnacles.

And so on. Williamson predicts that the genomes of insects with caterpillar-like larval stages will tend to be larger than those without, but the data indicate, if anything, a trend in the opposite direction. His predictions for specific insects don't pan out, nor do his predictions about the genome size of velvet worms and many other cases. If I read the paper right, not one of Williamson's many predictions actually goes his way. In some cases, he appears to cite genome size data that line up with his hypothesis, but miss citing similar organisms that contradict it.

So that would appear to be that. Indeed, as the authors of the latest PNAS paper mention, one might have thought so years ago, since these very authors have shot down some of Williamson's work before. That's the real problem here. I have a lot of sympathy for people who are willing to be spectacularly wrong, but that starts to evaporate when they don't realize that they've been spectacularly wrong. Williamson appears to have had a fair hearing for his ideas, and as far as I can tell, they've come up well short. And while we need brave renegades, cranks are already in long supply.

There's a constant running battle in the drug industry between the two kinds of pharmaceutical companies: the ones who discover the drugs first, and the ones who sell the drugs cheaply after the patents have expired. It surprises me still how many people I run into (outside my work) who don't make that distinction, or who don't even realize that there is one.

But the generic industry is a very different place. Their research budgets are far smaller than the ones at the discovery companies, since they're only dealing with drugs that everyone knows to already work. Their own research is directed toward satisfying the regulatory requirements that they're making the equivalent substance, and to finding ways to make it as cheaply as possible. And some of them are very good at it - some ingenious syntheses of marketed drugs have come out of the better generic shops. Of course, some real head-shaking hack work has, too, but that you can find everywhere.

The tension between the two types of company is particularly acute when a big-selling drug is nearing its patent expiration. It's very much in the interest of the generic companies to hurry that process along, so often they challenge the existing patents on whatever grounds they can come up with, figuring that the chances of success jutify the legal expenses. Since the 1984 Hatch-Waxman act, there's been an even greater incentive, the so-called "Paragraph IV" challenge. A recent piece in Science now makes the case that this process has gotten out of control.

After four years of a drug's patent life, a generic company can file an Abbreviated New Drug Application (ANDA) and challenge existing patents on the grounds that they're either invalid or that the ANDA doesn't infringe them. (This, for example, is what happened when Teva broke into Merck's Fosamax patent, taking the drug generic about four years early). If the challenge is successful, which can take two or three years to be resolved, the generic company gets an extra bonus of 180 days of exclusivity. The authors of the Science piece say that this process is tipped too far toward the generic side, and it's cutting too deeply into the research-based companies. (As noted here, that's rather ironic, considering the current debate about such provisions for biologic drugs, where some parties have been citing the Hatch-Waxman regime as a wonderful success story in small molecules).

This all took a while to get rolling, but the big successes (such as the Fosamax example) have bred plenty of new activity. There are now five times as many Paragraph IV challenges as there were at the beginning of the decade. Teva, for example, which is one of the big hitters in the generic world, had 160 pending ANDAs in 2007, of which 92 were running under Paragraph IV. Here's a look at some recent litigation in the area, which has certainly enriched various attorneys, no matter what else it's done.

Under Hatch-Waxman, a new drug starts off with five years of "data exclusivity" during which a generic version can't be marketed. The Science authors argue that the losses from Paragraph IV now well outweigh the gains from this provision, and that the term should be extended (which would put it closer to those found in Europe, Canada, and Japan. They also bring up the possibility of selectively extending data exclusivity case-by-case or for certain therapeutic areas, but I have to say, this makes me nervous. There are too many opportunities for gamesmanship in that sort of system, and I think that one goal of a regulatory regime should be to make it resistant to that sort of thing.

But I do support the article's main point, which is that the whole generic industry depends on someone doing to the work to discover new drugs in the first place, and we want to make sure that this engine continues to run. Politically, though, anything like this will be a very hard sell, since it'll be easy to paint it as a Cynical Giveaway to the Rapacious and Hugely Profitable Drug Companies. But speaking as someone working for the RHPDCs, I can tell you that we are indeed having a tougher time coming up with the new products with which to exploit the helpless masses. . .

Here's a most interesting graph from the latest issue of Nature Reviews Drug Discovery. It's from an article on trying to discern trends from broad-scale literature analysis, and it's worth a separate blog post of its own (coming shortly). But after yesterday's discussion of whether there are too many graduates in science and engineering, this looked useful.

Note, for example, the ramp up in NIH funding in the late 1950s/ early 1960s (a very large change in percentage terms), which was followed by a similar surge in doctorates granted. The late-1990s funding increases seem to be having a similar effect near the end of the chart.

Note also the well-publicized drug drought - but the historical perspective is interesting. We've clearly fallen off the 1970-2000 trend line of increasing drug approvals, but we seem to be stabilizing at roughly a 1980s level. The argument is whether that's where we should be or not. We have all these new tools, but all these new worries. Lots of new targets, but fewer good ones like the old days. Many new tools, but plenty of difficult-to-interpret data generated from them. And so on. But 1985 is apparently about where the balance of all these things is putting us.

Here's one to get your attention: there's been a lot of arguing (on this blog and others) about the continual talk of shortages of scientists and engineers. That's a little hard to take for the number of people who've been laid off from this industry over the last two or three years and who often are having trouble finding a new position.

A study from Rutgers and Georgetown now says, though, that there is no such shortage. Here's the PDF, so you can check it out for yourself. The intro:

A decline in both the quantity and quality of students pursuing careers in science, technology, engineering, and mathematics (STEM) is widely noted in policy reports, the popular press, and by policymakers. Fears of increasing global competition compound the perception that there has been a drop in the supply of high-quality students moving up through the STEM pipeline in the United States. Yet, is there evidence of a long-term decline in the proportion of American students with the relevant training and qualifications to pursue STEM jobs?

In a previous paper, we found that universities in the United States actually graduate many more STEM students than are hired each year, and produce large numbers of top- performing science and math students. In this paper, we explore three major questions: (1) What is the “flow” or attrition rate of STEM students along the high school to career pathway? (2) How does this flow and this attrition rate change from earlier cohorts to current cohorts? (3) What are the changes in quality of STEM students who persist through the STEM pathway?

What they're finding is (again) that there's no shortage of graduates - in fact, quite th opposite, unfortunately for wages and employment. One worrisome thing, though, is that at some point in the mid-to-late 1990s the top-performing students at both the high school and college level began to jump ship from the science/engineering fields. There are several possible explanations, but the one that comes to mind is that students are looking ahead a bit and don't like the prospects that they see and/or are lured by other fields that seem more attractive.

More on this later - for now, here's some commentary over at Science which shows that the arguing has already begun.

Here are a few more of those questions that medicinal chemists have to deal with from time to time. Most of these have no definitive answers (which is why they keep coming up!)

1. You're making a compound that looks to be important in the project - maybe even the clinical candidate, if things go right. But there's a step in the synthesis which - while it does work - is clearly not something that's going to scale up too well. You need more compound right now, and you can push things through. But you're eventually going to have to ditch that step (unless this compound gets overtaken by another one), so. . .when's the right time to worry about that?

2. Your compound series is in a pretty crowded patent landscape. In fact, another application has just published that really looks to be breathing down your neck. Of course, that means the work in it was done a year and a half ago (or more). Can you assume that Company X has followed the same course that you have, and has already investigated the series you're working on? Should you drop them, or go in in the chances that six months from now another application will drop that covers you like a tarp?

3. You're finally writing up one of your old projects for publication. But it's been a while, and the details of what happened are not as sharp as they were when thing were going on. What's more, on looking the work over, you realize that there are some obvious gaps in it, stuff that didn't look that way at the time, but sure does so now. You can write things up to make it look more coherent, but only by rearranging the way it really happened. Where do you draw the line?

4. Your lead compound is ready to go into toxicology testing, the last big step before declaring victory and naming it as the development candidate. Trouble is, there's something funny about it in rats. They just don't get the blood levels that mice and dogs do, and your tox people would really, really rather run the tox study in rats (since that's the standard, and what they have the most comparison data for). Update: I mistakenly switched rodents mentally this morning on the train, now they're switched back to what they should be). You can get the blood levels up to where they need to be - but only by using a dosing vehicle that might have problems of its own, and that the toxicologists haven't had much experience with either. What to do?

Now here's a completely weird idea: a group in Korea has encapsulated individual living yeast cells in silica. They start out by coating the cells with some charged polymers that are known to serve as a good substrate for silication, and then expose the yeast to silicic acid solution. They end up with hard-shell yeast, sort of halfway to being a bizarre sort of diatom.

The encapsulated cells behave rather differently, as no doubt would we all under such conditions. After thirty days in the cold with no nutrients, the silica-coated yeast is at least three times more viable than wild-type cells (as determined by fluorescent staining). On the other hand, when exposed to a warm nutrient broth, the silica-coated yeast does not divide, as opposed to wild-type yeast, which of course takes off like a rocket under such conditions. They're still alive, but just sitting around - which makes you wonder what signals, exactly, are interrupting mitosis.

The authors tried the same trick on E. coli bacteria, but found that the initial polymer coating step killed them off. That's disappointing, but not surprising, given that disruption of the bacterial membrane with charged species is the mode of action of several broad-spectrum antibiotics.

"Hmmm. . .so what?" might be one reaction to this work. But stop and think about it for a minute. This provides a new means to an biological/inorganic interface, a way to stich cell biology and chemical nanotechnology together. If you can layer yeast cells with silica and they survive (and are, in fact, fairly robust), you can imagine gaining more control over the process and extending it to other substances. A layer that could at least partially conduct electricity would be very interesting, as would layers with various-sized pores built into them. The surfaces could be further functionalized with all sorts of other molecules as well for more elaborate experiments. No, this could keep a lot of people busy for a long time, and I suspect it will.

Johnson & Johnson's CEO has given an interview to the Financial Times explaining his company's strategy with acquisitions. And right now, that strategy is. . .not to make acquisitions. They see partnerships as making a lot more sense:

“The cost of developing compounds has become so high and become so risky that we are looking to share the risks and opportunities and find more and more partnerships.”

J&J has been putting this into practice recently, taking equity stakes in several different companies. In the case of Elan and Crucell, interestingly, the company has agreed to standstill provisions, in order to make it clear that they're not just on the first step to an outright acquisition any time soon. It's interesting that this would be coming from Johnson & Johnson, since in many cases they've been one of the less destructive acquirers in the business already. (Well, with some exceptions, like when they took over Scios).

The temptation to compare this policy with Pfizer's is almost overwhelming, but the two companies are in very different positions. For one thing, J&J has their medical devices and diagnostics businesses, which are both profitable and run on different rhythms than their pharma side. Even more importantly, they also aren't locked into a grow-or-die situation, needing larger and larger infusions of revenue to meet the expenses which get larger every time they go out and buy those revenue streams, which mean that they need to go buy some more and then. . .

The article says that J&J has no deals under consideration right now, but that this style of deal-making is definitely how the company plans to operate. There's definitely enough risk to be spread around - I just hope that there's enough reward for everyone, too.

I've been occupied all morning with voodoo. Well, the technical name for it is catalytic hydrogenation, but let's call it for what it is: witchcraft. It's a widely used reaction in organic chemistry, and you can use it to reduce all kinds of different functional groups on your molecules. But once you get off the well-traveled roads, it's all jungle drums at midnight.

One reason we chemists like this reaction so much is that it's simple. You add some dark insoluble powder to your compound - which is some metal like palladium, platinum, nickel or the like, adsorbed onto carbon black or another solid. Then you add solvent and put the whole thing under an atmosphere of hydrogen gas. That soaks into the metal particles, your compound sits on them and gets magically reduced, and after a while you filter everything off and there's your clean, transformed product.

Most of the time. You'll note that I've skipped over a lot of variables there. For one thing, there's the choice of metal catalysts. Pt and Pd get the most use, but they come on a variety of solid supports. Carbon, alumina, barium sulfate, calcium carbonate. . .they all act differently. And don't stop with those guys: nickel's not to be ignored, then rhodium's available, and even ruthenium if you want to crank up the pressure. The pressure of all that hydrogen, there's another variable. Just a balloon on top, atmospheric pressure? Or put in a thick glass bottle on a shaker and turn it up to 50 pounds per square inch? Higher, in a metal apparatus? And what temperature did you have in mind? Ambient, or would you like to heat things up? Remember, as the pressure goes up, so does the temperature you can run the solvents up to.

Ah yes, the solvents. A lot of the time you see this work done in methanol or ethanol, but the reactions will often go quite differently in ethyl acetate or even something less polar. I've even seen some done in dichloromethane, although that somehow just seems wrong. Acids often have a profound effect on things, particularly if there's a basic amine in your compound.

And I haven't mentioned poisoned catalysts yet, have I? A bit of lead, or the addition of (non-protonated) amines or sulfur-containing compounds can dial down the reactivity of a lot of these metals - often down to zero, but sometimes to a useful level that you can't reach any other way. And then there's transfer hydrogenation, where you don't use the gas itself, but let some other compound give up hydrogen inside the reaction and transfer it over to your substrate. Paraformaldehyde, formic acid, phosphites, cyclohexene - all of those will work, and they can all work differently.

So. . .how many variations are we up to? Do you want to use 5% palladium on carbon in methanol, room temperature at 50 psi? Or platinum oxide in acetic acid at 50 degrees? Rhodium on alumina, ethanol, 100 psi at 100 C? Or wet 10% platinum catalyst with formic acid? That should get you started on this simple, well-known reaction. I've run 22 of them in the last two days, with the assistance of the H-Cube reactor, and I have to say: I'm about hydrogenated out.

I wrote about this topic a few years ago, and thought I'd update it. Many chemists find themselves looking at a periodic table and wondering "How many of these things have I personally handled?" My list is up to nearly 45 elements (there are a couple that I've got to think about, one-off catalyst reactions from twenty-two years ago and the like). And there are at least 29 that I hope to never use at all, since they're radioactive and I'm generally not in the mood for that. So what does that leave me?

Well, I've never used beryllium, although it's not that I'm tapping my foot waiting for any. It's pretty toxic stuff, for the most part, and there are hardly any organic chemistry reactions that get near it. That means that I can't even think what I might use it for, and I could easily go my whole career without seeing any.

The next lowest molecule weight element I haven't messed with (excluding unreactive neon, which you at least get to see in its excited state) is probably scandium. That whole first column of transition metals is pretty useless for organic chemists, to be honest (Yttrium? Lanthanum?), and I've never seen any reactions that leapt out at me as things I had to try. No, if the answer is scandium, it must have been a pretty odd question.

Next up, I haven't used either of the G twins, gallium and germanium. They're not too well studied compared to their family members above and below: aluminum and even indium are more widely used than gallium, and silicon and tin show up in organic labs a million times more often than germanium. But with those relatives, you'd have to think that there's something interesting that can be done with these, so it depends on whether anyone finds out what that might be during the rest of my chemistry career.

And right next to these is arsenic, which I've also managed to avoid. It's famously poisonous, although it's really not worse than a lot of other things that get used much more often. But again, there's not a lot of compelling chemistry to be done with the stuff, not that I know of, anyway, and there are always those unfortunate nomenclature problems to be dealt with, especially if you have a British accent.

Krypton I've never had a use for, and I'd have to rate the chances as very low indeed. In the next row, I've handled strontium chloride, but only to make red-colored flames for a school demonstration show. I have yet to touch yttrium, as mentioned above, and I've managed to miss zirconium so far as well. There are actually a number of organometallic reactions that use that one, so it's at least a real possibility. Niobium I have yet to encounter, and at the rate it's used, I probably never will. Cadmium's another toxic beast - there are some old reactions that use organocadmiums, but I can't think when I saw a modern reference that used any of them, and I don't see this one in my future, either. Antimony I might use if I never need some horrible superacid. Tellurium, well. . .there would have to be a pretty good reason, given its reeking, nose-wrinkling sulfur and selenium relatives, but someone might yet come up with one. Can't rule that one out, unfortunately.

Now we're getting into the heavy metals, and a lot of gaps start to appear. Has anyone in an organic chemistry lab ever used hafnium or tantalum? Didn't think so. The best candidate for "something I could use, but haven't" in this bunch is osmium. The tetroxide is a very useful reagent that I just haven't had the need for. It wouldn't surprise me if that's the next addition to my list. I've no desire whatsoever to use thallium. It's part of a short run of nasties that you hit right after the jewelry metals - you have your platinum, then gold, and you think you're in the high-rent district, and suddenly it's mercury, thallium, and lead right in a row. Reminds me of the way towns were stuck next to each other in New Jersey.

And as far as the lanthanides, well, I've used cerium as a TLC stain, and once I used samarium iodide - which, true to its reputation, didn't work. None of the others have I touched, and unless I need some funky NMR shift reagent, which fewer and fewer people do these days, I don't see it happening. There are a lot of funny rare earths down there, but little reason for an organic chemist to go digging around among them.

Weirdest element I actually have handled? Xenon would have to be the winner - I've used the difluoride, and yes, that was the recourse of a desperate chemist. But it did work to turn a silyl enol ether into an alpha-fluoro ketone, so I can't say anything bad about it, other than its rather penetrating smell, which I probably should have taken more care not to experience. . .

Organometallic reagentss come from large tribes, and there are always wild cousins up in the hills. A good place to look for the livelier ones is in the simplest alkyl derivatives, and you should go all the way down to the methyls if you want to know their real character. Ignore the halides. Methylmagnesium bromide you can get in multiliter kegs; they might as well sell it in Pottery Barn.

Dimethylmagnesium, though, is not an article of commerce. I've made it myself. So although it's definitely something you want to keep an eye on, I can't very well say that I won't work with it. And the other metals? Dimethyl mercury I will not get within yards of, for very well-founded reasons. Trimethylaluminum is a flamethrower extraordinaire, with a solid reputation among pyromaniacs. I've used the stuff, although I wasn't whistling while I was syringing it out. Handling it in solution, as I did, is less stressful than using the pure stuff - I'd definitely want to sit down and think about that one.

But neat dimethyl zinc. . .no, I don't think so. A colleague of mine made some in graduate school, and came down the hall to us looking rather pale. He'd disconnected a length of rubber tubing from his distillation apparatus and seen it go up in immediate, vigorous flames. "This stuff makes t-butyllithium look like dishwater" is the statement I remember from that evening. You can buy the pure stuff from Alfa, if you're inclined to run a head-to-head comparison. Do make sure to post the video on YouTube; that's as close as I want to get.

One problem is that it's a pretty volatile compound, boiling at 46C, so there's plenty of vapor around to start a party. The diethyl analog is a bit better, but it's nearly as pyrophoric. The Library of Congress discovered this in the 1980s and 1990s, during a long-running project to deacidify old documents. The diethyl zinc reacts with the acid in aged wood-pulp papers, neutralizing it, lightening the color, and stiffening the paper, so you'd think it would be ideal. Well, except for the instant-bursting-into-ravenous-flames part. Making sure that all the reagent was gone before opening the hatch, that was rather important. The pilot plant for this process suffered from some regrettable explosive bonfires before the whole idea was abandoned. Interestingly, one of the biggest problems seems to have been that the treated books were (at least at first) rather odorous, and some colored book covers were initially affected. You can sense a certain testiness about these issues in the Library's final report on the subject:

It has also been established that tight or loose packing of books; the amount of alkaline reserve; reactions of DEZ with degradation products, unknown paper chemicals and adhesives; phases of the moon and the positions of various planets and constellations do not have any influence on the observed adverse effects of DEZ treatment.

You'll notice that the LOC didn't even bother with the dimethyl compound, and I think I'll take a tip from them.