That’s because I’ve experienced the alternative, as I’ve detailed here before. If most of the lab fire stories you hear start out with the phrase “We had this solvent still. . .”, the rest of them all seem to begin with “We had this summer undergrad student. . .” (You can imagine the flame-filled end to any story that starts out with a summer student distilling some solvent – that Venn diagram leaves you with no way out at all).

No, after watching an undergrad next door to me kick a four-liter jug of pyridine all over the floor, causing a shimmering wave of unspeakable pyridine vapors to almost knock me off my feet. . .and after watching another one walk away for two hours after setting up a reduced-pressure DMSO still, which inadvertently turned into a high-pressure apparatus and blew DMSO and calcium hydride all over the inside of a hood. . .and after watching them charcoal reactions by plugging heating apparatus straight into the wall outlet instead of into the Variac. . .and, well, you get the idea.

I should add that I was no great shakes as a summer undergrad myself. I did a summer after my sophomore year with Tom Goodwin, but didn't get a great deal accomplished (through no fault of his!) Then after my junior year, I worked with Dale Boger, back when he was at the University of Kansas, but I mostly (and rather slowly) found a list of conditions that don't work for inverse electron demand Diels-Alder reactions. But although I spilled some generous amounts of solvent, I didn't set anything on fire.

No, we're going to have a calmer and more productive summer around here. I have my student working on a problem I've had a longstanding interest in, one that needs some variables chased down and figured out. With any luck, enough data will be generated to make for an interesting publication late in the year, and everyone will come out ahead.

Now there’s another one potentially coming up. Expectations are building for a thrombin receptor antagonist compound, SCH 530348. And I have a history with this one, too: while the labs down one hallway from me were discovering ezetimibe, down the other hallway they were laying the foundation for this one. There’s a big difference, though, in the way I saw the two.

This thrombin antagonist is an unlikely drug for several reasons. For one thing, its structure is not the sort of thing most medicinal chemists would go out of their way to make. But there’s a good reason for that: to a first approximation, it wasn’t made with medicinal chemistry in mind. 530348 is based on a natural product called himbacine, whose fame, such as it is, rests on its properties as a semi-selective muscarinic antagonist. And that’s how Schering-Plough got interested in this class of compounds; thrombin had nothing to do with it.

At the time (early to mid 1990s) the company had a team working on Alzheimer’s disease, and I’ll go ahead and mention again that I was one of the people involved. (Five minutes on SciFinder would tell you that, anyway). We were quite interested in selective muscarinic antagonists, particularly for the m2 subtype, and himbacine was at the time one of the more selective compounds with that profile. So one of the group leaders at the company, Sam Chackalamannil, decided to synthesize it and do some SAR around the structure.

That was no small undertaking. Himbacine’s not one of the most complex natural products by any means, but it’s no stroll to the beach, either, especially when compared to the usual sorts of drug structures. It took a lot of time, a lot of ingenuity, and (most importantly) a lot of effort to do it. And I. . .well, I thought this was a terrible idea.

I really did. By the time himbacine itself got made, the project team had muscarinic compounds that were more selective and more potent (and a lot easier to make, to boot). I would listen to Chackalamannil’s people presenting their long, difficult routes during meetings, and I’d sit there imagining the company going slowly bankrupt if everyone adopted this approach, the revenue slowly sinking as the number of JACS communications rose. I couldn’t see the point, and although I don’t think I ever quite had the nerve to say so to Chackalamannil himself (hi, Sam!), I said it to plenty of other people.

So, is it time for me to eat crow? Well, one plateful, at least. Some of the himbacine analogs hit in the high-throughput screen for thrombin activity, to everyone’s surprise, and some further compounds (now shed of their muscarinic activity) were even better. The drug discovery effort culminated in 530548, which now might be about to benefit a huge number of people and make the company a ton of money, if everything goes well.

Of course, if these things hadn’t hit in the thrombin assay, I could have remained secure in my opinion. After all, they were never worth very much as muscarinics, as far as I know. (Of course, our muscarinic compounds, in the end, never were worth very much as Alzheimer’s drugs, which is something to keep in mind). So that’s the question: how likely is it for molecules like this to work? It’s very hard to answer that, but given this data point, I guess the answer is “at least a little more likely than I thought”. The very fact that they didn’t look like most other things in the screening deck was probably in their favor. I still think that these compounds were a long shot, but this is a business that lives on long shots. This one came through, and congratulations to everyone involved.

Talking to such folks (interested, but with no particular training in science) gave me some good practice in explaining the work. It helps that the kind of work I do is actually fairly easy to explain. There are a lot of details – as with any branch of science, the closer you look, the more you see – but I haven’t run across any key concepts that can’t be communicated in plain language. (It also helps that medicinal chemistry, as it’s actually practiced, uses an embarrassingly small amount of actual mathematics).

The toughest things to deal with are the parts of the field that actually touch on physics and math. My vote for the hardest everyday phenomenon to explain at anything past a superficial level is magnetism. So that means that explaining how an NMR machine works is not trivial. At least, explaining it in a way that a listener has a chance of understanding you isn’t – a while ago, I took up the challenge to try to explain it here in lay terms, and I haven’t done it yet, for good reason.

Explaining statistical significance is doable, but going much past that (principal components, the difference between Bayesian and frequentist approaches) takes some real care. And, of course, when you open the hood on chemical reactivity, the mechanisms of bond-forming and bond-breaking, you quickly find yourself in physics up to your armpits. It’s easier to stipulate, openly or by assumption, that there are such thing as chemical bonds, and that some of them are stronger than others. You don’t want to start answering a question about why one group falls off your drug molecule easier than another one does, only to find yourself fifteen minutes later trying to explain the Pauli exclusion principle. Counterproductive.

But the basics of medicinal chemistry can be sketched out pretty quickly, which makes some of the more curious listeners wonder, after a while, why we aren’t better at it. The best example I can give them is to advance a quick, hand-waving explanation of, for example, how compounds get into cells. Then I point out that that explanation is unnervingly close to the best understanding we have of how compounds get into cells. The same holds for a number of other important processes, way too many of them.

And that's why drug discovery is simultaneously frustrating and fascinating. We know huge numbers of things, great masses of detail that can take years to piece together. And it's not enough. Some of the most important puzzle pieces are still weirdly ill-defined, and there are probably others whose existence we haven't even realized yet. I'd be willing to bet that if you scanned the whole history of pharmaceutical discovery, you'd find people at every point thinking "You know, in any thirty years they should have all this figured out". But the years go by, and they - we - don't. Give it another thirty years, you think?

"The company disclosed that it would also be closing its 50-year-old natural products drug discovery operation based in Madrid after a Merck executive inadvertently included the plan in a PowerPoint presentation to an audience that included Merck employees."

Smooth move. I'm sure some interesting e-mails were exchanged around Rahway and Madrid after that one. When, when will we get the powerful regulatory oversight of PowerPoint technology that the masses have cried out for these many years?

The main thing I remember about Merck's operation in Madrid was when they made a big splash about ten years ago with a weird looking indole/quinone thing that directly activated the insulin receptor. It made the cover of Science and all sorts of press releases, and my biology colleagues starting pestering me immediately. "Hey, you chemists keep saying that there's no point in running a small-molecule screen against the insulin receptor!"

Well, as it turned out, we were right. I assured my co-workers on the next floor that the Merck compound was one of the least likely drug candidate structures I'd ever seen, and that I'd be intensely surprised if it went anywhere. In fact, I told them, seeing it on the cover of Science actually decreased the likelihood that it was anything useful. If Merck really had a small-molecule insulin mimetic, I reasoned, the program would be a real stealth bomber, for fear of sending all sorts of other companies into the same chemical space too quickly. This one had all the signs of the people involved saying "You know, the only thing this stuff is good for is getting on the cover of Science"

So it proved, eventually. The compounds never went anywhere. It looks like the most recent natural product-derived compound that Merck got onto the market was Cancidas (caspofungin), and that was seven years ago. Mevacor (lovastatin) will stand as the modern high-water mark of Merck's natural product work - presumably from now on.

I’d like to see a map of the world with country size dependent on the number of scientific publications and patents – perhaps you’d want to use publications per capita, or per educated capita. That's a cartogram, and although there are plenty of interesting ones on the web, I haven't found that one yet. The US would loom large, that’s for sure. Japan might be the most oversized compared to its geography, although Singapore would also be a lot easier to pick out. Western Europe would expand to fill up a lot of space, with Germany, England, and France (among others) taking up proportionally more room inside the region and (perhaps) Spain and Portugal taking up somewhat less. Switzerland would swell dramatically.

South America would be dominated, I think, by Brazil, even more than it is on the map. You’d be able to find Argentina and Chile, but I think some other countries (like Venezuela) would dwindle in comparison. Africa, as it does so often in maps of this kind, would appear to have been terribly shrunk in all directions, with a few countries – Egypt, South Africa – partially resisting the effects. Moving on to Asia, India would appear even larger than it is, unless you went for the per-capita measurement to cut it back down a bit, and China would be a lot more noticeable than it was ten (or especially twenty) years ago.

Another region that would basically disappear would be the Middle East and most of the rest of the Islamic world. Iran would hang in there, smaller but recognizable, and you’d be able to find Pakistan, too. But the Arab countries (with the minor exception of Egypt) would nearly vanish. The figures from the Organization of the Islamic Conference (the multinational group involved) show that from 1995-2005, the Islamic countries contributed 2.5% of all the peer-reviewed scientific papers. That’s all the more interesting when you consider the amount of potential funding that washes around that part of the world.

This disconnect has been noticed by the region’s scientists, as well it might. The OIC has designated a committee of science ministers to help with a multiyear plan for modernizing things, but no one’s sure if any real money will be forthcoming. According to this Nature article (headlined "Broken Promises"), the OIC countries allocate less than 0.5% of their GDP to research and development. Most of the money promised just to fund that science committee never showed up. Lip service is, of course, a feature of politics (and politicians) everywhere, but I don't think I'm out of line if I suggest that it's very close to an art form in that part of the world.

And that's a very short-sighted approach. Many of these countries are sitting on huge amounts of money at the moment, which should be invested against the day that their oil runs out (or against the day that the world decides that it's not as desperate for oil as it once was). That latter day will, presumably, be hastened along by the countries who spend more on research. . .

There's long been a suspicion that a lot of Alzheimer's pathology is driven by inflammation cascades, and although evidence has been mixed to date, this would seem to be good evidence for that idea. (More on this in another post). This wasn't a prospective study - they didn't enroll people just to test this idea - but a huge number of VA patients were studied retrospectively, and the authors appear to have done as much as possible to control for other variables. Of course, in an observational study like this one, you can't control for the biggest possible confounding factor: what if there's something about patients who end up taking NSAIDs more often that also keeps them from developing Alzheimer's? That certainly can't be ruled out, but I don't think there's room for that in most of the headlines. It's going to be tempting for worried patients to start taking ibuprofen to prevent dementia - and that just might work, still - but we really can't be sure without plenty of prospective trial data.

Of course, not everything is good for preventing Alzheimer's. You can apparently add statins to that list. An examination of aging Catholic clergy (mostly nuns) showed no correlation at all between statin use and the development of the disease. This is one of those long-running studies that ends with death and subsequent brain histopathology, too, so it's pretty hard to argue with. Intellectually demanding work, though, does perhaps show a protective effect. Interestingly, this effect was even stronger in the cohort of patients that scored lower in assessment of overall intelligence, which makes sense in a way. (Cue the arguments about whether general intelligence exists, whether it can be measured, and if so, whether it's being measured in the correct way).

On the ever-profitable herbal front, you see all sorts of claims made for Gingko biloba extract and cognitive function, and there are a lot of contradictory studies (many of which, unfortunately, aren't worth much). This latest one won't help much - in the intent-to-treat analysis, no effect was seen. When they controlled for how well patients stuck to the treatment, then some correlations emerged between taking the extract and slower rates of memory loss. Unfortunately, a correlation (at the same level of significance) emerged with stroke and associated TIAs. My prediction: the ginkgo biloba sellers will trumpet the first set of statistics, assuming they need recourse to any data at all, and ignore the second one completely.

Such is the current state of Alzheimer's. To be honest, none of these studies (or most of the others in the same issue) would have been out of place back when I was working in the field in the early 1990s. The field awaits its breakthrough, and has been waiting for a long time. . .

And when you get your compound in, they arrive in various forms. Glass or plastic bottles are the norm, naturally, with the occasional irritating (but presumably necessary) sealed-glass ampoule. But after some time in the lab, you can tell some of the suppliers from across the room. For example, the Japanese company TCI sends a lot of its compounds in normal-looking glass bottles, but these are first put inside capped plastic containers, like larger translucent versions of the ones that 35mm film probably still comes in. And once you taken them out, their glass bottles have these odd plastic labels on them which come up around the screw cap and are perforated around the cap’s border. On the labels, they also have that same thin, fussy, serif font that the Japanese have been using for Roman-style letters for decades (since the war?) and is only in recent years disappearing from their world.

Maybridge, British vendor of all kinds of odd stuff, often sends its compounds in these weird little squat brown-glass bottles with small black caps on them. They must have the world supply of that particular bottle shape tied up, since I’ve never seen one anywhere else. It most resembles the small bottles that solutions for injection are packaged in. So many of the company’s catalog items are in such bottles (or even smaller ones) that it seems wrong somehow when you come across a huge (huge for Maybridge) hundred-gram bottle with their label on it.

Most of the suppliers have neutral-sounding names like those above. They could be chemical companies, vendors of kitchen cabinets, real estate trusts, who knows: Maybridge, Oakwood, Lancaster (now gone, and their blue labels with them). And some of them are unmistakably in the chemical supply business, but rather blandly named (Pharmacore, for example, or Chembridge). Some names are, perhaps, mistakes: the namers of Asinex, for example, seem to have been unaware that the closest Engish word is “asinine”, which means that they have to hope for people to pronounce that “s” as if it were a “z”. (I should mention that both Asinex and Chembridge indulge in one widely hated practice: putting no useful information on their tiny vials other than a catalog number or bar code – Bionet (Key) is a similar offender).

In this dull company, I’m always glad to see the weirdos. I miss the now-purchased-away British supplier called Avocado – green labels, naturally – and always wondered who named them and why. Tyger Scientific makes me wonder if there’s an English major in somewhere at their founding, fond of William Blake. And there’s one company that came into the industry under the glorious name of, I am not making this up, “Butt Park”, and many are the chemists they’ve made stand puzzled in front of the supply cabinet. (I'd provide a link, but I can't find a direct one, and Googling it can be a real minefield).

I refuse to consider that name a mistake. That's a feature, not a bug, and I wish that there were more competition in the category. I would proudly and purposely send business to, say, Batshit Chemical Supply, Inc., even if they back-ordered me every single time.

As the folks at the InVivoBlog note, it sure was hard, from one perspective, to see that one coming. After all, Claritin (loratadine) has an exemplary safety record and has been on the market for many years now, and Singulair (montelukast) has been selling in the billions of dollars as a stand-alone drug. No doubt many people have taken, and are taking, the two as separate pills. So you combine them and get a "not approvable": right.

The In Vivo people speculated that this might be a safety problem, since the agency has been mighty jumpy about that area recently, but Merck has now told them that safety and tolerability weren't raised in the FDA letter.

Well, what does that leave? Manufacturing? Hardly possible, given the way that these two drug substances are already being cranked out. That, as far as I can see, leaves good old efficacy. You could always argue that putting the two compounds into one pill improves patient compliance, etc., if the combination itself is useful in the first place. But in this case, I'd guess that the problem is that the combo has turned out to offer no benefit over either drug taken alone. Hard to make a case under those circumstance, it is.

And if you look into the history of a Singulair/Claritin idea, that appears to be just the problem. As the Wall Street Journal's Health Blog notes, the companies had already found no benefit for seasonal allergies, compared to either drug standing alone. Supposedly they were able to come up with some sort of nasal congestion data (what a joy that must be) that showed an edge this time, but yikes - how desperate do you have to be to take things to that point, after you've already seen no benefit in the main endpoints?

So why are Merck (and Schering-Plough) spending money on this kind of last-gasp line extension? Surely there are better places to burn cash. I've never been sympathetic to the argument that money spend on promotion is somehow stolen from R&D, but this sort of thing is another matter. Stupid R&D most definitely steals money from smarter R&D, and here's some of it that's made off with the swag.

As you would imagine, the work from the 1960s and 1970s has an otherwordly feel to it, considering the hardware that was available. And that brings up another thing common to the early years of new technologies: when you look back on them from their later years, you wonder how these people could possibly have even tried to do these things.

I mean, you read about, say, Richard Cramer establishing the computer-aided drug design program at Smith, Kline and French in nineteen-flipping-seventy-one, and on one level you feel like congratulating his group for their farsightedness. But mainly you just feeling like saying “Oh, you poor people. I am so sorry.” Because from today's perspective, there is just no way that anyone could have done any meaningful molecular modeling for drug design in 1971. I mean, we have enough trouble doing it for a lot of projects in 2008.

Think about it: big ol’ IBM mainframe, with those tape drives that for many years were visual shorthand for Computer System but now look closer to steam engines and water wheels. Punch cards: riffling stacks of them, and whole mechanical devices with arrays of rods to make and troubleshoot stiff pieces of paper with holes in them. And the software – written in what, FORTRAN? If they were lucky. And written in a time when people were just starting to say, well, yes, I suppose that you could, in fact, represent attractive and repulsive molecular forces in terms that could be used by a computer program. . .hmm, let’s see about hydrogen bonds, then. . .

It gives a person the shudders. But that must be inevitable – you get the same feeling when you see an early TV set and wonder how anyone could have derived entertainment from a fuzzy four-inch-wide grey screen. Or see the earliest automobiles, which look to have been quite a bit more trouble than a horse. How do people persevere?

Well, for one thing, by knowing that they’re the first. Even if technology isn’t what you might dream of it being some day, you’re still the one out on the cutting edge, with what could be the best in the world as it is. They also do it by not being able to know just what the limits to their capabilities are, not having the benefit of decades of hindsight. The molecular modelers of the early 1970s did not, I’m sure, see themselves as tentatively exploring something that would probably be of no use for years to come. They must have thought that there was something good just waiting right there to be done with the technology they had (which was, as just mentioned, the best ever seen). They may well have been wrong about that, but who was to know until it was tried?

And all of this – the realizations that there’s something new in the world, that there are new things that can be done with it, and (later) that there’s more to it (both its possibilities and difficulties) than was first apparent – all of this comes on gradually. If it were to hit you all at once, you’d be paralyzed with indecision. But the gap in the trees turns into a trail, and then into a dirt path before you feel the gravel under your feet, speeding up before you realize that you’re driving down a huge highway that branches off to destinations you didn’t even know existed.

People are seeing their way through to some of those narrow footpaths right now, no doubt. With any luck, in another thirty years people will look back and pity them for what they didn’t and couldn’t know. But the people doing it today don’t feel worthy of pity at all – some of them probably feel as if they’re the luckiest people alive. . .

Diazomethane’s a very useful reagent, but it has to be treated the right way. You can’t buy it – no one will ship the stuff – so you have to make it fresh. (There are several such reagents). For many years there have been chemicals in the catalogs whose only real use has been to generate diazomethane when needed. Generally this involves treating some nasty N-nitroso compound with base in ether, then distilling over the ether solution of the reagent, which is a distinctive bright yellow.

There’s where some of the trickiness comes in. That diazo group is looking for an excuse to revert back to nitrogen gas, which process comes with an inevitable no-substitutions side order of kaboom. The chemist’s job is to not give it that excuse. That means that you can’t heat the stuff up, you don’t make it very concentrated, and you don’t even expose it to sharp or rough surfaces, because that can be enough right there. They sell distillation glassware specifically for diazomethane preps, with weirdly glossy ground-glass joints.

You can keep your yellow solution stockpile in the freezer for a while, and the temptation is always to make a lot of it so you never have to do it again. That leads to phenomena like the big flask of the stuff left behind when someone leaves the grad school group. One of those surprises (“Is this yellow stuff what it looks like it is? How long has it been in here? And who the hell made it, anyway?”) was the cause of a new lab inspection requirement while I was getting my degree. You couldn’t leave until someone determined that you weren’t passing on any explosive bequests.

Of course, sometimes you honestly need a lot of these things. One of the guys in my group was in that situation early in his total synthesis. One summer afternoon, the power went out in the labs during a thunderstorm, and the head of our safety committee came rolling a big cooler of dry ice down the hall. “Anybody need to store something in the cold?” was the call. “Well,” I said, “we’ve got a couple of liters of diazomethane solution.” “That’s not very funny,” he said. “That’s because it’s not a joke”, I replied, and we moved to the front of the line.

So, what’s the stupidest way to handle the stuff? That’s the story told to me by a colleague. He attests that when he was in grad school, he looked across the hall to see someone involved in making a goodly amount of diazomethane – in a large standard ground-glass-joint apparatus. Oh, dear. How the guy was going to get his collection flask off without running the risk of grenading everything, that was the question. As my friend watched in disbelief, the guy reached up to just twist the darn thing right off. . .and it was stuck. A frozen joint – just the perfect time for it. (This is the point where the audience for this story began to bury their heads in their hands).

My colleague swears that he then watched this maniac pick up a propane torch to sweat the joint loose. I believe that someone may have stopped him in time, but I think the teller of this tale decided to adjourn for lunch at some distant location right around then, so I can’t vouch for the outcome. But if anyone has a more drooling, slack-jawed approach to an ether solution of diazomethane than running a propane torch over it, I’d like to know what it is. Short of maybe using it as an HPLC solvent, I’m out of ideas.

What's Cordaptive, or whatever it's called, anyway?
That's Merck's newest cardiovascular drug - although the active ingredient isn't new. It's niacin, also known as vitamin B3. It's been known for many years that niacin can both lower LDL cholesterol and raise HDL, as well as lowering triglycerides - in fact, it's probably one of the only things that can do all of those significantly at the same time.

So this is a rip-off, then? Merck's trying to sell vitamin B for $20 a pill?
No, it actually isn't, at least not to the extent you're thinking. The problem with niacin as a cholesterol therapy is that you have to take whopping amounts of it to see an effect. And there's a side effect - flushing of the face, which is basically uncontrollable blushing that can last for hours in some cases. That may not sound like much, but the great majority of people who take niacin at these levels have a problem with it, and a lot of people discontinue the therapy rather than put up with it. If the drug is taken for a few weeks, the flushing reportedly eases off some, but not everyone makes it to that point. By all reports, it's very irritating - and since patients can't feel their cholesterol being high, but can feel their faces burning and turning red, they solve the problem by not taking the niacin.

So why doesn't Cordaptive do the same thing?
A lot of people have tried to find a way to keep the lipid effects of niacin and get rid of the flushing. Merck added a prostaglandin receptor antagonist, laropiprant, to try to block the pathway that leads to the vascular effects. And it seems to help quite a bit, which made the combination a potential winner. Abbott already has Niaspan, a slow-release version of niacin, which also has reduced flushing problems and does about $600 million of sales a year. Niacin therapy itself seems to be pretty safe, although you do want to make sure that liver and kidney function are normal before you start, so the only big question has been what blocking that DP1 receptor might do on the side: can you take that pathway out without causing more trouble?

Well, can you?
Apparently not. Actually, that should be "apparently there isn't enough evidence to say yet" - that's probably more in the spirit of the FDA's letter. They want to see more information about the drug. Problem is, the FDA treats this (properly) as a matter between the agency and the drug company, so they aren't saying what the problem is. And Merck, for its part, isn't saying, either. Investors feel rather left out in these situations - perhaps the most striking one in recent years was Sanofi-Aventis's absolute wall of silence for months about why the FDA wasn't approving their potential blockbuster Acomplia (rimonabant).

Why's this so unexpected, if there wasn't enough evidence given to the FDA?
Well, there seems to have been enough evidence in the same pile of data for the European Union, whose regulators approved recommended the drug for approval a few days ago. Merck must have felt reasonably confident that they'd get the same treatment here. No such luck. And as just mentioned, we don't know if the problem is not enough evidence of efficacy, not enough evidence of safety, or a bit of each.

Why don't you people just make cholesterol-lowering drugs that work better, then, so there's no doubt about efficacy?
Would that we could. Statins basically only lower LDL - they don't raise your HDL. And if you push the statins too hard, patients start coming down with rhabdomyolysis, and you don't want that - ask Bayer. Raising HDL has proven to be a real challenge, too. There are a lot of ideas about how to do it, but the most obvious ones aren't working out too well - ask Pfizer.

OK, then, why don't you just make safer versions of what you already have?
Would that we could. But in almost every case, we have no idea of how to do that. For the most part, either the safety concerns are tied up with the beneficial mechanism of the drug, or they're occurring through side pathways that we don't understand well and don't know how to avoid. And some of those are things that you don't even get a read on until your drug gets out into the market, which is no way to do things, either.

So, why is the drug business considered such a safe bet?
Now, that one I don't have an answer for. Unless it's the conviction that people are always going to get sick, which I guess is a pretty safe bet. And that's coupled with a conviction, apparently, that we're always going to be able to do something profitable about that. And some days, I have to wonder. . .

Unfortunately for both him and for me, his Advanced Inorganic course ended up scheduled for 7:40 AM back in early 1983. I started out my college career with a barrage of classes at that hour, and made every one of them. My sophomore year, I only skipped one class, and I waited for the lightning bolt to descend even for that one. But my junior year I had a professor or two whose lectures could be safely (even profitably) missed, and I began to get in the habit.

Teague wasn’t in that category, though. His lectures were fine; it’s just that they took place so early in the morning. My roommate David and I, both chemistry majors, found it harder and harder to summon the activation energy needed to make it out of the thermodynamic sinks of our beds. Dr. Teague’s threat to come over and teach the class in our dorm room didn’t quite do the trick (while lying there in bed, actually, the idea had a certain appeal). But his threat to start giving top-of-the-morning quizzes did. I showed up, and kept showing up. First year of grad school, now that’s where I started slacking off in my classes in earnest. But not all of the professors I had that year could communicate the facts of their specialty as well as Dr. Teague could for his.

The lab part of the course, that I would have shown up at 6 AM for. I don’t know how he’s done it in recent years, but 25 years ago (not possible, that), we could do pretty much any lab procedure that Dr. Teague would sign off on. There was a requirement that we do at least one low-temperature one, one high-temperature one, one metal complex, and so on. So the dozen or so of us in the class would root around through Inorganic Syntheses or the like, looking for interesting stuff. And there’s plenty of it in there, let me tell you.

In my case, the most memorable included the preparation of fluorosulfonic acid from scratch. Scratch means you start from concentrated hydrofluoric acid, a fine substance for the spirited undergraduate chemist to become familiar with. I can still hear the peculiar whine that solid KOH pellets make when you toss them into a plastic dish of the acid – they’ve a pretty short half-life in there, I can tell you. And I also made the magnesium analog of ferrocene – magnecene, I guess you’d call it – by one of those don’t-be-afraid-of-the-obvious routes: heat some magnesium turnings to about 600 C in a tube furnace, and pass fresh cyclopentadiene monomer vapors over them. Works great. And while you shouldn’t be afraid of the paper synthesis, red-hot magnesium metal is something else again.

While I was thus engaged, my classmates were setting off thermite reactions, making phosgene from carbon tetrachloride (chromium trioxide, five hundred degrees, nothing to it), and preparing titanium tetrachloride from the ground up. (I can’t recommend that particular prep – the liquid “tickle-four” comes out bright green from being around 1 molar in dissolved chlorine gas, so you’re going to want to redistill it, most likely). We learned a fair amount of inorganic chemistry, and more than a fair amount of lab technique. As evidence for that, we all survived.

Whether the latest generation of undergrads will get these kinds of experiences, I don't know. But I'm glad I did, and I'd like to thank Warfield Teague for providing them.

Of course, these deals have two sides to them. I don’t know what it’s like in Takeda back in Japan – my contacts inside the Japanese pharmaceutical industry aren’t extensive. But I think that some of the people at GSK (where I do know a lot of people) are wondering just what motivated their company to spend $720 million on Sirtris rather than on them.

It’s a fair question, even though I don’t have a problem myself with the Sirtris deal (as I said yesterday). But the sirtuins themselves are targets that anyone can work on, and you’d assume that a big outfit like GlaxoSmithKline could, if they wanted to, make a big push into the area and find some interesting things. So why didn’t they? The most obvious reason would be Sirtris had already done a good deal of that work, and it was more economical for GSK to buy it than to redo it. Another possibility is that the chemical space for drug-like hits in that area may not be very spacious, and that Sirtris may have already carved out a good piece of that real estate.

There’s also a bit of Glaxo history to deal with. The company had already, about fifteen years ago, decided to make a great big push into a promising new research area: nuclear receptors. They set up a whole research institute and did a huge amount of good science trying to figure out how these things worked, what they were good for, and how to get drugs that affected them. I got interested in the field in the late 1990s, and it became clear to me very quickly that Glaxo’s effort was the most serious of the bunch (and that included some really substantial research going on at Merck, Lilly and some other outfits). The company had teams of people who seemed to do nothing else than study the structures of these things, generate reams of X-ray data, synthesize huge lists of ligand molecules of every kind you could want, and so on. Just run "Glaxo nuclear receptor" through PubMed to see what I mean.

And what did it get them? From what I can see, not much. Avandia (rosiglitazone) is a nuclear receptor ligand (for PPAR-gamma), but its activity had already been discovered, and it was in clinical trials without a known mechanism. Figuring out how it worked was one of the Glaxo team’s early triumphs. But Avandia has turned out to be famously troublesome, and no others have come to market, despite multiple tries in the clinic. The huge amount of time and money the company spent generated a lot of interesting science, but appears (at least to me) to have brought in not one dime of revenue. (No doubt someone from GSK will correct me if I’m wrong).

So you can see how the company might be wary of starting a big internal effort to explore a massive, complex, and risky new field of biology. Politically and psychologically, it’s probably easier for them to structure this in terms of an acquisition.

I lean toward the latter, but I’ve long had a place in my heart for sirtuin research and its potential. It’s still a long shot, but it’s one of the most intriguing ones in the history of medicine. Actually, from one perspective, you wonder how long a shot it is: a biochemical pathway that seems to extend healthy life in yeast, roundworms, flies, and mice would seem to have some odds of doing the same thing in man. A lot of drug programs have been started with a lot less backing them up, albeit for rather less earth-shattering indications.

Of course, Sirtris hasn’t officially been targeting life extension drugs, at least not in the near term. A number of these potential life-extending biochemical pathways are tied up with insulin signaling, which makes sirtuin-targeted drugs a natural for diabetic therapy as well. Sirtris has reported encouraging data for just that indication. If a sirtuin-based drug is going to make it to market, that’s a good bet for how it’ll do it. I note, though, that the company has also applied for orphan-drug status for resveratrol itself for a rare muscle disorder. But they don’t own that parent compound, just its use in this case – the diabetes work is being carried on with second- and third-generation analogs that address some of resveratrol’s problems. (It’s not a particularly stable compound, for one thing).

Once one of these drugs is approved, it’ll have the biggest, strangest potential for off-label use that anyone has ever seen. Oh, that’s going to be something to watch. GSK is well aware of this – I’m not saying that it’s part of their business plan, but when you see their head of drug discovery talking to Forbes and tossing the word “transformational” around, you know that they’ve thought beyond a replacement for Avandia. The Wall Street Journal headlines it like it is: “Glaxo to Buy Sirtris in Bet on Antiaging Reseach”.

That’s the truth, all right, and it’s going to be fascinating to watch things develop. As I was saying here the other day, a drug for aging is a perfect example of something the FDA has absolutely no idea of how to approach. Well, it’s not just the FDA, come to think of it: how on earth would you design a Phase II trial for life extension? How long would it take? What’s your clinical endpoint? And further on, how long will you want to monitor your Phase III patients (recall Pfizer’s recent follow-up of Exubera trial participants? How long will it take before you could be sure that some horrible bargain wasn’t struck along the way?

That’s the lurking fear behind all this research, fit to give Leon Kass the shakes. Life extension tends to give some people the same “Things Man Was Not Meant to Know” shivers as (for example) germ-line genetic manipulation. I’m tempted to cue the theramin music in the background, but I can’t really make fun of this attitude, since I understand where the uneasiness is coming from. In all these cases, we’re looking at real alterations of what we think of as human. Personally, I think there’s room for improvement in what we think of as human, but I agree that we should reach for those improvements carefully. And I can see how the very thought could strike some people as coming close to crazy.

But we’re going to find out. That’s the real import of the GSK news: the money is there to find out what’s possible in this field. I’m happy to hear it. But then, I was a bit euphoric back in 2003 when this news started breaking, and I’ve never really lost that feeling. We shall see.