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

Derek Lowe The 2002 Model

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

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

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January 30, 2009

Roche Goes Hostile - Or Does It?

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Posted by Derek

An analysis of the offer here, from the Dealbook blog at the New York Times. This one leans toward the idea that the whole thing is an attempt to move Genentech's board to accept a deal, rather than go through with a real tender offer. Either way, someone's clearly been reading Delaware securities law (and the original affiliation agreement between the two companies) very closely indeed.

No matter what the intent, not everyone thinks it's it going to work. And as with the Pfizer / Wyeth deal, the cost of insuring Roche's debt have gone up steeply in response to all this.

Meanwhile, at the WSJ Health Blog, they're wondering how this is all going down with Genentech's "brainy, headstrong" scientific staff. Maybe Roche figures there aren't many other places to go? More on this Monday when some of the dust settles.

Comments (9) + TrackBacks (0) | Category: Business and Markets

10,000 Hours To Drug Discovery?

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Posted by Derek

I see a fair number of people reading Malcolm Gladwell’s Outliers while I’m commuting. I haven’t read it myself yet, but it seems that a key feature of his case is the “10,000 hour rule”, the idea that many people who are extremely good at a given task have spent at least that long perfecting their skills. (This derives from the work of Anders Ericsson and Herb Simon over the last thirty or forty years).

One of the more perceptive reviews of Gladwell’s book I’ve read is by Michael Nielsen. He brings up the problems that many scientists have had with some of Gladwell’s past work, and according to him, if you weren’t happy with Blink or The Tipping Point, you may well not be happy with this one. (Of course, if you didn’t like those, you probably won’t read this one!) Of course, as a scientist, when you read about something like the ten-thousand-hour rule, the first thing you ask yourself is “Hmm. I wonder if that’s true?” But as Nielsen points out:

There are, of course, many provisos to the 10,000 hour rule. As just one example, to acquire mastery in an area, it’s not enough to just practice for 10,000 hours; the person practicing must constantly strive to get better. Someone who practices without pushing themselves will plateau, no matter how many hours they practice. I suspect many scientists fall afoul of this proviso, putting in enormous hours, but mostly doing administrative or drudge work which doesn’t extend their abilities.

But that said, Nielsen goes on to talk about some scientists who have done great work well before their 10,000 hour mark. These people were working at discontinuities, sudden discoveries that didn’t necessarily build on the past, so they didn’t have as much of a tradition or art to master. A thorough grasp of 19th-century physics didn’t help people much when it came time for quantum mechanics. It wouldn’t be surprising, Nielsen says, if a disproportionate number of great discoveries in science fell into this category.

Now, which category does drug discovery fall into? We have a fair amount of art to be learned and experience to be gained, true. But there’s another factor that confounds things: sheer luck. I think that the fundamental issues of drug design are still so poorly understood that no amount of skill can compensate for them. I’m thinking of difficulties like designing compounds that have good oral absorption or blood-brain barrier penetration – sure, there are guidelines, and there are things that you learn to avoid, but once past those it’s a crap shoot. And then there’s toxicity – you learn pretty quickly not to put known landmine groups into your molecules, but after that, you just have to cross your fingers and hope for the best.

These things also mean that there’s a good amount of work to be done that doesn’t extend a person’s abilities, as the quote above has it. The worst of it is being outsourced these days, the well-known “methyl ethyl butyl futile” stuff, but there’s still a lot of pickaxe work that has to be done in any drug project. It would be a fine thing if ten thousand hours of hard work and practice allowed someone to come in and make nontoxic molecules, but they often have to be discovered by trial and error, and more of the latter.

That said, I take Nielsen’s point about putting in good hours rather than empty ones. As much as possible, I think that we should try to do things that we haven’t done before, learn new skills, and move into untried areas. Try not to get butyl-futiled if you can possibly avoid it; it’s not going to do you much good, personally, to set up another six or eight EDC couplings. There are times that that’s exactly what needs to be done, but don’t set them up just because you can’t think of anything else. This gets back to the point I’ve made about making yourself valuable; anyone can set up amide reactions, unfortunately. Maybe some of the time we spend learning our trade is spent learning how to avoid falling into all the tar pits and time-wasting sinkholes we have.

Comments (23) + TrackBacks (0) | Category: Who Discovers and Why

January 29, 2009

"I Will Cherish the Personally Autographed Book Forever. . ."

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Posted by Derek

The research scientists in a drug company often don't mesh well with the marketing people (two cultures, and and all that). For an entertaining look at why this might be the case, try this from BNET Pharma, and just shake your head in amazement. . .

Comments (23) + TrackBacks (0) | Category: Things I'm Glad I Don't Do

Opportunity Costs

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Posted by Derek

We’re seeing an example right now of one of the big costs of a drug company acquisition. While the Pfizer / Wyeth deal winds along, with all the regulatory and financial details being slowly worked out, what happens in the R&D organizations?

Well, at Wyeth, I’d imagine that things have slowed down a great deal. No one knows what the future will be like, what parts of the company will stay, and which people will be asked to stay with them. How do you make plans under those conditions? For many people, the project they’re working on is now very much a secondary consideration.

Even outside the personal level, there are a lot of paralyzing influences. The same uncertainties about individual jobs apply to development projects. Some of what Wyeth is working on surely overlaps with what Pfizer’s already doing. So which project goes forward? Not both of a matched set, that’s for sure. There are some projects at both companies that are dead in the water, but no one can be sure which ones, and no one will know for some time to come.

That’s because you can’t really start ironing out these details until the deal goes through. Legally, Pfizer and Wyeth are separate companies, and there are a lot of difficulties involved in sharing information in such depth. Even when that eventually happens, there are going to be plenty of other things to work out. Let’s say that Project Y from Wyeth looks to be in better shape than the corresponding Project Y-Prime from Pfizer, so it goes on through. Fine! But under whose rules does it proceed?

Every company has its own culture about these things – the criteria that are used to recommend a compound to the clinic, the ways those boxes are filled in, the sorts of people who have to sign off on them. A project caught in the middle can stall while all these details are cleared up, losing months (or even a year or two) in the process. You can imagine the disconnects: you guys did check this compound for hERG activity, right? With what assay? And with what cutoff? That’s not the one we use, anyway; we’ll have to run it again, and get that signed off on by. . .hmm, well, by someone, we’ll figure out who’s in charge of that sort of thing soon, about the same time that we figure out who reports to them. Now, about your formulations work. . .you used what, again?

No, all this has a ferocious price, when you measure it in opportunity costs. The people caught up in all this could be doing something much more productive with their time, for sure. This sort of thing doesn’t show up on the books. And the longer the process drags on, the worse it’ll be.

Comments (23) + TrackBacks (0) | Category: Business and Markets | Drug Development

January 28, 2009

Science and Its Values

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Posted by Derek

Dennis Overbye had an essay in the science section of the New York Times yesterday, entitled "Elevating Science, Elevating Democracy". That gets across the spirit of it pretty well; it's one of those soaring-rhetoric pieces. It starts off with a gush of at-last-we-have-Obama, but what op-ed in the Times doesn't these days? We're going to be sweeping that stuff into piles and pulling it down out of the trees for months. (Before sending me an e-mail, keep in mind that I'd have a similar reaction no matter whose name was involved; I'm just not a person with high expectations from politicians).

But once he gets past the genuflections, I don't disagree with Overbye's main points. He says that science has a reputation of being totally results-oriented and value-neutral, but wants to point out that there are values involved:

"Those values, among others, are honesty, doubt, respect for evidence, openness, accountability and tolerance and indeed hunger for opposing points of view. These are the unabashedly pragmatic working principles that guide the buzzing, testing, poking, probing, argumentative, gossiping, gadgety, joking, dreaming and tendentious cloud of activity — the writer and biologist Lewis Thomas once likened it to an anthill — that is slowly and thoroughly penetrating every nook and cranny of the world."

We forget what a relatively recent and unusual thing it is, science. In most societies, over most of human history, there hasn't been much time or overhead for such a pursuit. And even when there has, most of the time the idea that you could interrogate Nature and get intelligible, reproducible answers would have seemed insane. Natural phenomena were thought to be either beyond human understanding, under the capricious control of the Gods, or impossible to put to any use. In retrospect, it seems to have taken so painfully long to get to the idea of controlled one-variable-at-a-time experimentation. Even the ancient Greeks, extraordinary in many respects, had a tendency to regard such things as beneath them.

So let's shed the politics and celebrate the qualities that Overbye's highlighting. Run good, strong, experiments. Run them right, think hard about the results, and don't be afraid of what they're telling you. That's what got us to where we are now, and what will take us on from here.

Update: a comment from Cosmic Variance.

Comments (11) + TrackBacks (0) | Category: General Scientific News | Who Discovers and Why

January 27, 2009

Pfizer and the Credit Crunch

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Posted by Derek

You might think that the Pfizer/Wyeth deal means that things are creeping back to normal in the M&A world. But the Wall Street Journal reports that Pfizer is having to pay about 8% for the money it's borrowing, and that the funds are due back in a year. There are also very significant clauses in the deal which make it contingent on Pfizer's bond ratings, etc., and will force the company to shell out if things don't go as planned. There's a 4.5 billion dollar breakup fee, for example, which seems to be about twice the usual contingency.

Meanwhile, Reuters notes that credit default swaps on Pfizer's debt have jumped, reflecting significant uncertainty about whether the whole deal will actually go through. Pfizer's likely to be downgraded even if things go smoothly, so this is going to be expensive from every direction. . .

Comments (42) + TrackBacks (0) | Category: Business and Markets

A Long Tail Indeed

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Posted by Derek

A reader reminded me of this paper, which I meant to blog on when it came out last year. The authors looked over the entire Chemical Abstracts Service registry file – in theory, every compound that’s ever been reported in the chemical literature – and asked how many different chemical scaffolds make up the organic chemistry part of the collection. (That ran to a bit over 24 million compounds at the time the paper was written).

You’d expect a power-law (“long tail”) distribution in a data set like this, and that’s just what they found. Among heteroatom-containing scaffolds, the most common 5% were found in about 75% of the compounds. In fact, it was even steeper than that – the most common 0.25% of the heteroatom frameworks made up half the compounds! The flip side of this is that about half of the known scaffolds occur only once, which is about as long a tail as you can get.

That’s almost completely accounted for by (1) the availability of certain starting materials, largely from petroleum and from natural products and (2) the interest in preparing a given framework. Put more crassly, it depends on how much it’ll cost (in time and money), and how much you expect to get back. As the authors put it:

” We believe the presence of this power law is quantitative evidence that the minimization of synthetic cost has been a key factor in shaping the known universe of organic chemistry.”

Tiny variations can send a given scaffold diving off the charts. Think, for example, about the usual steroid framework – there have been a huge number of variations worked on that, since they’re of medical interest and the starting materials are available (thanks, in the early days, to some Mexican yams and their biggest fan). But imagine going in and replacing one or two of those carbon atoms with nitrogens: whoosh, down you go. Many of those frameworks have hardly been touched at all, partly because they’re quite difficult to make. You’d have to have a very good reason to go after them, and that hasn’t presented itself. Meanwhile, the vast numbers of indoles, piperazines, and piperidines in drug molecules help to perpetuate themselves.

The same goes, and even more so, for general compound shapes (heteroatoms or all-carbon). The authors found 836708 different framework shapes, but that breaks down rather sharply: half the compounds are accounted for by 143 frameworks, and the other 836565 make up the other half. I’ll let the authors have the last word:

”It seems plausible to expect that the more often a framework has been used as the basis for a compound, the more likely it is to be used in another compound. If many compounds derived from a framework have already been synthesized, these derivatives can serve as a pool of potential starting materials for further syntheses. The availability of published schemes for making these derivatives, or the existence of these derivatives as commercial chemicals, would then facilitate the construction of more compounds based on the same framework. Of course, not all frameworks are equally likely to become the focus of a high degree of synthetic activity. Some frameworks are intrinsically more interesting than others due to their functional importance (e.g., as a building block in drug design), and this interest will stimulate the synthesis of derivatives. Once this synthetic activity is initiated, it may be amplified over time by a rich-get-richer process. . .”

Comments (5) + TrackBacks (0) | Category: Chemical News | Drug Industry History | The Scientific Literature

January 26, 2009

Pfizer / Wyeth: Different This Time?

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Posted by Derek

The Pfizer/Wyeth deal is on, and I would really, really prefer to write about something else this morning. The main thing we can hope for is that the company has decided, just possibly, that its previous takeovers didn’t quite work out the way that they were supposed to on paper, and has resolved to run this one differently. The fact that Wyeth doesn’t have One Huge Drug (the way Warner-Lambert had Lipitor, or Pharmacia-Upjohn had Celebrex), gives me at least a little hope. But, as people were pointed out in the comments to Friday's post, there's no way that you can make this deal work without a lot of layoffs.

What’s frustrating about the way Pfizer’s been going is that I don’t think they’ve necessarily been trying to destroy things. It’s just that they’re so massive that it’s hard for them to pick anything up without crushing it. I could be wrong about that – perhaps there’s an official strategy document somewhere that reads:

“Buy company. Strip of immediately valuable pipeline assets and turn over to Marketing Hordes. Fumble with rest of drug discovery pipeline for a few years while trying to figure out where in the massive scheme of things its parts might fit. Realize that the stuff you bought is going off patent – how time flies! Realize that you have too many sites and too many people – close 'em down, lay 'em off. Realize that, for some reason, you have nothing new ready to sell. Go back to step one. Repeat for as long as there's another drug company.”

If this hasn’t been the plan, it might as well have been. Do it differently this time, guys, if you can. The industry can’t take this stuff forever. If people had internal organs that behaved the way Pfizer has the last ten years, we’d be developing drugs to treat them.

Comments (64) + TrackBacks (0) | Category: Business and Markets

January 23, 2009

The Real Hazards of the Lab

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Posted by Derek

A run of bad accident news today, and all of the same kind. The Chemistry Blog has the story of a fatality in the labs at UCLA. The short and painful details are: inexperienced student, t-butyllithium, flammable clothing, and panic (as in not running toward the safety shower).

This is very sad to hear about, and as with so many lab accidents, one of the saddest parts is how easily it could have been prevented. t-BuLi is, of course, a well-known fire starter, and the student did know about that problem. But one of the keys to working with dangerous substances is to think through what you’ll do if something goes wrong. For a pyrophoric compound, that means knowing where the nearest fire extinguisher and safety shower are. It’s very easy to panic when something goes wrong, but if you’ve rehearsed what to do beforehand, you have a much better chance of doing the right thing in tough circumstances.

I pass this along to the students who read this site, and I’m sure the other experienced lab workers here will agree: always think “OK, what’s the worst thing that can go wrong with this reaction?”, and think about what you’ll do if that happens. Fire? Explosion? Sudden leak of nasty toxic stuff? Think it over. Anyone working in a laboratory should always know where the nearest fire extinguisher is. That is, the nearest appropriate one – if you’ve got a separate Class D model for metal fires, or even just a sand bucket, then when you need it you’re really going to need it. And everyone should know where the nearest safety shower is, because no one ever just sort of needs to use one of those. I’ve had to run and pull one once in my career, and let me tell you, it was a damned good thing that I knew where to go when the chips were down.

The other news I have was communicated to me privately, so I won’t go into details other than to say that it appears to be another fatality, this time involving inhalation exposure to trimethylsilyl diazomethane. The problem with these sorts of reagents is that you might think that they’d cause breathing trouble immediately, but you’d be wrong. Diazomethane, phosgene, methyl bromide and others can actually take hours to kill a person, and for a good part of that time, the only symptoms might be a slight cough. But serious lung damage can be coming on slowly during that period, and by the time it’s clear that there’s a problem it’s usually too late to do very much about it. Unfortunately, in some cases, it’s too late right from the start, but that takes quite a bit of exposure, and indicates a serious mistake somewhere along the line.

Anyone who works with such volatile and damaging reagents needs to be completely aware of what they’re doing, and to only handle them under good ventilation. I’ve used such things many, many times in my career, without incident, and so have most working organic chemists. But we should never lose respect for what we’re holding in our hands.

I’m not trying to scare beginning chemists out of doing lab work. It has it hazards, but so does driving to work in the morning or cutting up food for dinner. (When I was in graduate school, my mother once expressed her worries about my lab work, but I told her that the most dangerous thing I did was to drive 650 miles back home on holidays). But every well-appointed chemistry lab is full of death in screw-capped bottles, and that bears thinking about. Random, unforeseeable accidents are, fortunately, very rare. But that means that the others didn’t have to happen, and that’s painful to contemplate.

Comments (65) + TrackBacks (0) | Category: Chemical News | Graduate School | Life in the Drug Labs

Pfizer / Wyeth: They're Going to Take Us All Down With Them

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Posted by Derek

Well, as most of you will have heard, the news this morning is that Pfizer has been in talks to buy Wyeth for several months now. So they must be serious about it, eh? That's been one of the deals tossed around as a possibility, so it doesn't come as a complete surprise. I guess what does surprise me is that the company really is going to continue their amoeboid lifestyle. But then again, what choice do they have?

I've said so much about Pfizer recently that I think everyone here knows my thoughts (and I was recently quoted in the New London newspaper The Day unburdening myself in similar fashion, which should ensure that I'll never get a job at the company). But what am I saying? Who thinks that Pfizer will be doing anything but shedding head count for several years to come?

Update: I have more comment on this, for a non-industry audience over at The Atlantic's new business site, where I'll be contributing some posts on the drug world.

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

January 22, 2009

The Great Acetonitrile Shortage

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Posted by Derek

Now here’s a news item that I’m pretty sure you haven’t heard about unless you work in or near a laboratory. We’re in the middle of an extreme shortage of acetonitrile, a common solvent. This has been going on since back in the fall, but instead of gradually getting better, it’s been gradually getting worse: major suppliers are sending out letters like this one (PDF).

What’s the stuff good for? Well, it’s used on a manufacturing scale in some processes, so they’re in trouble for sure. Acetonitrile is a good solvent, since it’s fairly powerful at dissolving things but still reasonable low-boiling. (That’s the nitrile functional group for you; there’s nothing else quite like it). It’s no DMSO, but then again, DMSO’s boiling point is three times a lot higher, and compared to acetonitrile it pours like pancake syrup. Nobody does industrial-scale chemistry in DMSO if they can possibly help it.

Those properties mean that acetonitrile/water mixtures are ubiquitous in analytical and prep-sized chromatography systems. This is surely its most widespread use, and is causing the most widespread consternation as the shortage becomes more acute. Many people are switching to methanol/water, which usually works, but can be a bit jumpier. But that’s not always an option. Labs working under regulatory-agency controls (GLP / GMP) have a very hard time changing analytical methods without triggering a blizzard of paperwork and major delays. In many companies, it’s those people who are first in line for what acetonitrile may turn up.

So why are we going dry on the stuff? There seem to be several reasons, one of which, interestingly, is the summer Olympics. The industrial production that the Chinese government shut down to improve Beijing’s air quality seems to have included a disproportionate amount of the country’s acetonitrile production (for example). A US facility on the Gulf Coast was shut down during Hurricane Ike as well. But on top of these acute reasons, there's a secular one: yep, the global economic slowdown. A lot of acetonitrile comes as a byproduct of acrylonitrile production, which is used in a lot of industrial resins and plastics. Those go into making car parts, electronic housings, all sorts of things that are piling up in inventory and thus not being turned out at the rates of a year ago.

So taken together, there’s not much acetonitrile to be had out there. We’ve seen some glitches like this in the past, naturally, since chemical production can depend on a limited number of plants and on raw material prices. When I was an undergraduate, I remember professors complaining aboiut the price of silver reagents during the attempted Hunt brothers corner of that market, for example. But this one will definitely be near the top of the list, and it could be months before the Great Acetonitrile Drought lifts. If you've been saving some in your basement, it’s time to break it out.

Comments (109) + TrackBacks (0) | Category: Analytical Chemistry | Chemical News

January 21, 2009

Nitromed: Someone Wants Them

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Posted by Derek

Remember that NitroMed / Archemix deal that I mentioned briefly back in November? Well, it's not going so smoothly. One of the largest NitroMed shareholders, Deerfield Management, objected to the whole idea, and proposed buying the company itself.

Last week the company adjourned its shareholder meeting until yesterday to consider the offer, and yesterday they adjourned again. Deerfield started off at fifty cents per share, and has slowly raised its offer to $0.80. You have to think that that's the sort of behavior that they would have objected to in some other suitor for the company, but hey. . .

Comments (1) + TrackBacks (0) | Category: Business and Markets

The Hideous Numbers of Compounds

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Posted by Derek

I was blithely throwing around the term “chemical space” in yesterday’s post. So, what am I talking about, and how much room is in there, anyway?

Let's narrow it down to organic compounds, to start with, or at least compounds that are mostly organic. A working definition, as far as people interested in biology and medicine go, might then be “the domain of chemical compounds compatible with living systems”. That excludes the red-hot reactive stuff and the unstable exploders, but leaves most everything else. Let’s also ignore macromolecules of various kinds and cut back to “drug-like” sizes – say, molecular weight 500 or less. That way we don’t have infinite numbers of polymers going off in all directions; that should help. And that leaves us with. . .?

A ridiculously large set of compounds, still. You can see how things get out of control pretty quickly if you just consider a building-block problem. Imagine breaking compounds down into simple units - an aryl ring, an ether, a tertiary amine, and so on. What sorts of numbers do you get when you start mixing and matching them? Well, there are an awful lot of possible building blocks. You could quickly fill out a hundred different examples of each of those three subunits, so there's one hundred to the third, or a million possible compounds without even exerting yourself very much.

This sort of thought experiment has been done several times. One estimate done by this fragment approach and considering only stable structures came in between 10 to the twentieth and ten to the twenty-fourth compounds that could potentially be prepared using known synthetic methods. (See here for another "how many compounds are possible?" paper, from a different angle - the group that did that work has followed it up recently, which will be the subject of another post sometime). Needless to say, that is considerably larger than the total number of organic compounds ever described in reality. There's not enough carbon, oxygen, and nitrogen on earth to prepare a vial of each of these, and where would you put the vials? The terrifying thing is that this is actually one of the lower estimates, and thus perhaps a very reasonable and conservative one. You can find ten-to-the-sixtieth estimates out there, which is a figure that cannot be dealt with by human efforts.

These sorts of numbers are why some people doubt the utility of just cranking out neat structures. But looked at from the other direction, the number of compounds we have available isn't nearly so impressive, so making new ones, especially long lists of new ones, makes a difference in what we actually have in hand. But is it a difference akin to buying a thousand lottery tickets rather than buying one?

Comments (13) + TrackBacks (0) | Category: Drug Assays

January 20, 2009

Diversity-Oriented Synthesis: Oriented The Right Way?

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Posted by Derek

Ever hear of Diversity-Oriented Synthesis? It’s an odd bird. DOS tries to maximize the number of structures and scaffolds produced from a given synthetic scheme – to find the most efficient ways to populate the largest amount of chemical space. In a way, it’s the contrapositive of natural product synthesis, which focuses all its effort into producing one specific molecule at a time. I should add that DOS isn’t about producing mixtures; its goal is discrete compounds, but plenty of them, and all over the map. (Here's more background from David Spring at Cambridge).

The point of this is to increase the diversity of compounds libraries for biological screening. And that’s traditionally been the concern of the drug companies, but (as far as I can tell) there’s very little DOS going on inside the industry. All the publications in the field, at any rate, seem to come from academia. Companies certainly do care about the diversity of their screening libraries, but they don’t seem to be addressing the issue through the “maximum diversity in the fewest steps” philosophy.

There’s a recent paper in Ang. Chem. that will give you a good flavor of what’s going on in this area. A group led by Adam Nelson at Leeds has published an interesting approach that relies on olefin metathesis. An ingenious use of protecting groups and sequential metathesis reactions builds up a wide variety of structural backbones pretty quickly. (Another key feature is the use of fluorous tagging for purification, which will be the topic of another future post around here). Metathesis was certainly a good choice, since that gives you a chance to form a lot of carbon-carbon bonds in a lot of ways, all using basically the same reaction conditions. In just a few steps (around five or six) they ended up with about 80 quite different scaffolds.

Stuart Schreiber, an early advocate of DOS, wrote up a “News and Views” piece for Nature about this paper, and he makes the case this way:

” The resulting products differ from the compounds found in most small-molecule screening collections. Typically purchased from commercial vendors, the compounds in such collections frequently lack chirality and are structurally simple. This means that they can bind to only a small number of biological targets. The compounds in commercial libraries also tend to be structurally similar — their 'diversity' is limited to variations in appendages attached to a small number of common skeletons. This undesirable combination of properties means that, although enormous numbers of compounds (often more than a million) are frequently tested in screenings, at great expense, in the case of undruggable targets relatively few biologically active 'hits' are found. In principle, a smaller library of compounds that contains a more diverse range of molecular shapes, such as those made by Morton et al., would provide both more hits for less money, and hits for the more challenging biological targets.”

I see where Schreiber is coming from, but there are some details being overlooked here. One big point is that smaller compounds actually tend to hit more targets, just not with as much absolute potency: that's the whole idea behind fragment-based drug design. Larger, more complex molecules tend to be more selective, but when they happen to fit, they can fit very well indeed. You need a huge pile of them to have a chance of finding one of those, though. (I think that a happy medium would be a DOS approach to not-very-large compounds, but that doesn't give you that much room to maneuver).

Another point is that the key thing about the collections you can buy is that they often depend on just a few bond-forming reactions. You get an awful lot of amides, ureas, and sulfonamides, since by gosh, those sure can be cranked out. To me, that’s the first thing that makes the Leeds compounds stand out: none of these classic library-making transformations was exploited. Unfortunately, the other things that make the Leeds compounds stand out aren’t necessarily good. For one thing, there are no basic nitrogens in any of the structures. The paper lists a big class of azacycles, but in every case, the nitrogens are capped with nosyl groups, which completely wipe out their character. And while it’s true that you can get biological activity without nitrogen, you’ll get a lot more with it. A useful extension of the chemistry would be to use some sort of (update: more easily) removable group on the nitrogens, so that each scaffold could be unmasked at the end – that would give you the basic nitrogens back, and you could then make a few amides and the like off of them for good measure.

The compound set is also heavy on alkenes, which isn't surprising, given the metathesis chemistry. There's nothing wrong with those per se, but it would be worth taking all the scaffolds through a hydrogenation reaction to saturate the bonds, giving you another compound set. Alternatively, if you want to be a real buckaroo, take them through a Simmon-Smith reaction and turn them into cyclopropanes - that could be messy, but cyclopropanes are very much under-represented in compound libraries, compared to how many of them could potentially exist. A bigger problem is that one of the linking groups the Leeds team uses is a silyl ketal. That’s not the most chemically attractive group in the world, nor the most stable, and as a medicinal chemist I would have avoided it.

That brings up another point about well, the point of these libraries. Schreiber makes the pitch that if we're going to do chemical biology on the tougher interaction targets (protein-protein, protein-nucleic acid, and so on), then we're going to need all the chemical diversity we can get. That's hard to dispute! But a lot depends on whether these compounds are meant to be in vitro tools, or real leads for drug discovery. You can put up with silyl ketals (or worse) if the former, but not for the latter. (Many medicinal chemists would say that if you have some functional group that you're just going to have to remove, then don't put it in there in the first place).

And that's the gap between academia and industry on this approach, right there. The in vitro tools, used to discover pathways and interactions, are more the province of the university labs, and the drug leads are more the concern of industry. As it stands now, the drug company folks look at many of the DOS libraries and say "Hmm. . .sort of, but not quite". That's probably going to change, and if I had to guess, I'd say that one way into industrial practice might be through chemical vendors. There are a number of companies who make their livings by offering unique building block compounds to the drug industry - as DOS matures, these people may sense a commercial opportunity and move in.

Comments (50) + TrackBacks (0) | Category: Chemical News | Drug Assays

January 19, 2009

Ten Years After: The Genomics Frenzy

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Posted by Derek

So it’s been ten years now since the peak of the genomics craze in the drug industry. Hard to believe! Looking back on these things, it can be hard to recapture the mood, since regretful hindsight keeps blurring the more painful parts. I know that a lot of companies would, in retrospect, rather have back some of the huge amounts of money they spent back in that era, but for every one of those, there’s a genomics company that wishes that they had something that hot to sell again.

Well, actually, that’s not true in every case, since several of those genomics players haven’t even lasted long enough to look back from this far. But at the time, at the time they looked as if they might end up owning the world. Not everyone believed that, true, but I don’t remember many people with the nerve to say so in public. The strongest misgivings went something like “We don’t know if this is going to work or not, but we have to be ready if it does”, which is a perfectly defensible position.

But that was rare – most of the stuff you heard, at least in press releases and the like, ran to “Genomatronic Corp. announces that it has now filed patent applications (a whopping load of patent applications) on another huge, important swath of the vital human genome (remember, there’s only one!), and reminds the industry that its back walkway is open on Tuesdays and Thursdays for Big Pharma to come crawling up it”. Over at Megapharm, Inc., their opposite number, the fear was quite real that the Genomatronics of the world actually were staking out all the deposits of gold, and that all the drug targets in the world were going to end up owned by someone else – like those other big drug companies that were daily announcing huge deals with Genomatronic et al.

It was easy for panic to set in. How much of the genome could possibly be left by now? We’d better do a deal while there’s something to buy! After all, when you got down to it, these folks were right – there’s only one human genome, and we’re only going to read it for the first time once, and all the drug targets that will ever exist are in there – right? So why would you sit there and watch the competition walk off with all the good stuff? Right?

Well. . .not as right as you’d think. The big splash of cold water, at least as I remember it, was when the Human Genome Project folks announced the total number of human genes, and it came in way below what some people had been estimating – like, ten times less. If you added up all the genes that people had claimed to have filed applications on up until then, it was well in excess of the number of genes that turned out to actually exist. This embarrassing patent excess was one problem (some of which could be explained by multiple filings by different companies), but the unexpectedly small number was the other one, and the more worrisome. How could there be so few genes when we knew there there were a lot more proteins than that? And so the importance of post-translational processes finally began to be appreciated by a wider public. It wasn’t “one gene, one protein” – it was “one gene, a bunch of proteins, and we’re not sure quite how or quite how many”.

Another set of problems came on a bit more slowly. The companies that did the whopper genomic deals came to realize that (1) even 50,000 genes was rather a lot, when you had no idea what most of them did, what pathways they fit into, what diseases they might be associated with, and what might possibly happen if you found a compound that affected their associated proteins, and (2) it didn’t look as if we were going to even get a chance to find out about that last part, because most of these things came up empty when you screened against them anyway. These were (and are) all major problems. We still have only fuzzy ideas of what a lot of genes actually do, and we still have a terrible time finding useful chemical hits against a lot of our new targets – more on these later; they’re perennial topics around here.

You still see breathless articles (particularly in the alternative press) about the amount of your own DNA that’s like, patented and owned by the big corporations, man, but the people who write these articles generally don’t know enough to realize that most of that stuff is irrelevant. The patent office has tightened up severely on its requirements for gene patents, and recent court decisions have called the whole idea of patenting DNA sequences into question (more on this later, too). And at any rate, most of these things would be on track to expire without anyone yet finding out what they might be good for.

So where are we now? So, in the end, there was no genomics gold rush, at least not in the way that everyone thought. The genomics players are out of business, or if not, they had to completely retool and find something else to do. Most of their patent applications were wastes of time and money, since they never issued, were generally hard/impossible to defend if they did, and are mostly heading for expiration without having made anyone a dime. The value of the genome is real, but it’s taken (and it’s still taking) a lot longer to realize it than anyone would have believed in 1999. If anyone was predicting this ten years ago, I missed it. It wasn't me.

Update: Keith Robison lived it from the inside, and tells the tale.

Comments (44) + TrackBacks (0) | Category: Drug Industry History

January 16, 2009

Short Items: Viral NMR, Alarming Rings, Cheap Reading, Etc.

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Posted by Derek

From PNAS, here’s an ingenious method that’s allowed NMR-based imaging of particles as small as viruses. I didn’t even think that this was possible – so now that it is, look for all kinds of variations on it over the next few years, as is the way of NMR techniques. Single-cell MRI? As the authors (from IBM) point out, this is a sudden 100-million-fold improvement in volume resolution compared to conventional NMR. It always makes me smile to see that things like this can happen.

This one should go into my “Things I Won’t Work With” folder immediately. Courtesy of Pat Dussault, whose lab has been turning out alarming stuff like this for some years now, we have six-membered rings made up of two carbons and four oxygens. There is no way to do that without putting on protective gear, needless to say – the only question is which stylish ensemble to wear.

James Tour unveils the off-road version of the nanocar.

And finally, I wanted to pass along this scientific reading suggestion to everyone. If you’re into magnetic resonance properties of silicon isotopes, you can read the book. After all, the list price is only $8539.00 (and don't forget, it's eligible for Free Super Saver Shipping!) But the rest of us can enjoy the Amazon reviews, which range from very satisfied customers (“My only question was whether one copy would be enough”) to very unsatisfied indeed. . .

Comments (22) + TrackBacks (0) | Category: Chemical News | General Scientific News

With A Straight Face, Yet

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Posted by Derek

Well, the researchers at Pfizer have apparently been told that the latest round of layoffs are it, but I get the impression that this reassurance isn’t necessarily widely believed. People there (and at other companies) have been told that everything is rightsized and on track before the ax comes around again. I certainly hope that this time it’s true.

But the sales force doesn’t look to be as lucky, since the latest report is that up to one third of the sales reps might be laid off. That’s always been a volatile part of any company, with a lot of turnover, but man, that’s a lot of turnover. It puts the 8% cut in research into some perspective, but what a nasty perspective it is.

And in the research labs – well, I know that executives are supposed to say these sorts of things. And I know that if you don’t, they’ll find someone who will. But I still have to pass on this quote from Pfizer’s head of research, Martin MacKay, which as far as I can tell was delivered with no grimaces or coughing fits:

"“We haven’t taken any hit on productivity. We haven’t missed any milestones,” MacKay said. “We are keeping the organization fully focused on the work we have to do.”

Comments (18) + TrackBacks (0) | Category: Business and Markets

January 15, 2009

The Blogroll

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Posted by Derek

This is long, long, overdue, but I've finally gone through the blogroll and cleared out the dead sites, of which there are (were) many. Stage Two will be adding news ones. I already have a list going, with an eye on getting them in this weekend, but I'd be glad to hear about others that I might have missed. Chemistry / biology / pharma / science blogs that I don't yet link to, anyone? Add 'em to the comments if you have some, and thanks!

Comments (25) + TrackBacks (0) | Category: Blog Housekeeping

Lilly Pays the Price

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Posted by Derek

Eli Lilly has been in trouble for some time now regarding off-label promotion of their antipsychotic Zyprexa – specifically, their sales reps seem to have gone around saying that it was useful in treating the dementia of Alzheimer’s patients, although there was no FDA approval for that indication. (Whether it actually is any good for that, or whether much of anything is, I don’t know).

Word is this morning that the company will pay a total of about 1.4 billion dollars to settle the regulatory and civil complaints. That appears to be the new record. The idea is to send a strong message to other companies about aggressive off-label promotion, and a billion dollars should certainly get attention. Lilly will also be operating under a special monitor for five years, which is no joke, either.

But still. . .this is going to happen again, at some point. As we run things in the US, physicians are free to prescribe medications as they see fit (and I have to say, I agree with that principle). Insurance companies can pay for these or not as they wish, but the doctors can write for what they like. Drug companies, on the other hand, can only market for the indications that they’ve been approved for, and in this gap you can lose 1.4 billion dollars.

Despite these problems, I think the lines need to stay about where they are, although this is always going to cause problems. There’s a temptation to try to broaden your market when you have only preliminary data – worse, there’s a temptation to broaden it when you have no data at all. That’s got to be kept in check somehow. If you want to mark the limits of my libertarian leanings, there’s one of them. I worry that if every company were free to market every drug for everything, the resulting free-for-all would drag us all back down to the level of the late-night infomercial hucksters. The potential profits are just too great; they’re a moral hazard, and they’re not commensurate with the benefits for society at large.

The only middle ground I can think of at the moment would be a category of “Some evidence exists for. . .”, which would be in between an approved and unapproved indication. Perhaps then the sales reps could mention it? Maybe not, though, because where would you draw the line for how much promotion you could do? How would we keep this from turning into a battle zone? And there are too many ways that it could be abused: running a few sloppy studies to try to get some arrows pointing the right way, for example, and then turning the marketing department loose. (You know, the sort of thing that critics of the industry figure that we do already). No, again, I think that the temptation would be too great.

So here’s a general principle: we need enough regulation in the industry to keep ourselves from turning into what our worst critics think we are already. Not the most stirring call to arms, but there it is.

Comments (14) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

January 14, 2009

Qi Gong and Placebo Effects

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Posted by Derek

I’ve been hearing from all sides since I took my swipe at Deepak Chopra et al. the other day. The biggest subgroup with a grievance have been the people who weren’t happy with my comments about Qi Gong.

Part of the problem is that “Qi Gong” means different things to different people, ranging from “Chinese-derived low-impact exercise program” to “manipulation of universal healing energies”. That’s a lot of ground to cover, but I obviously have no problem with the first of those. Exercise is clearly beneficial in a number of different ways. I go to a gym myself, and emerge with sore muscles and a glow of self-righteousness.

But it’s hard to get away from that second definition. Different practitioners put different amounts of woo into it (as Orac puts it), but if you just go grab pages off the web or brochures from a local class, odds are very good that you’re going to start hearing about energy fields and such. And that’s where I get off. I have yet to see any convincing evidence for any such “energy lines” or “concentrations of the life force” (whatever that is) that show up in a lot of (semi-)mystical exercise programs.

If the people boosting Qi Gong and the like stick to claiming that exercise is good, and that these are good ways to get people to exercise, then fine. If they want to claim that Qi Gong is more effective than other sorts of exercise programs, then that’s fine, too, because we can subject that to empirical tests: blood pressure, muscle strength, joint flexibility, per cent body fat, resting heart rate, fasting glucose and triglyceride levels. So far, I haven’t seen anything that convinces me that it is – many of the studies that claim this seem to me to be very small and poorly controlled. The ones that address these issues tend to be a wash, or to show the reverse. But post some literature references and we’ll talk.

But claiming greater effectiveness gets tricky, because many of the people who do that aren’t just saying that Qi Gong (or what have you) is more effective for physical reasons. It’s a quick slide into the syrup from here, and in no time we’re aligning our energies and tapping into ancient wisdom. (I’m not that good a customer for ancient wisdom, myself. I don’t think that people were any wiser or more virtuous in the past, however misty and distant, and given the mixed-up course of history, I think that anything really ancient that’s survived has probably done so by accident as much as anything else. But that’s another subject).

And any of these comparisons will have to deal with the placebo effect, which is what I was getting at with my proposal for the Don Ki Kong protocol. There are, no doubt, patients that will show more benefit from an exercise program that they believe comes from the Ancient Orient than they would from a very similar set of moves that just got marketed in Santa Barbara. Some other patients may well show the reverse, depending on their attitudes. If you’re going to claim specific benefits for Qi Gong (or any other such system), you’re going to have to show that it isn’t due to such effects. Is it something that still works whether you believe in it or not? If belief is important, do the details of what you believe matter or not, or is it just a general placebo effect that depends on thinking that something beneficial is underway?

We have enough confusion with placebo effects already with our supposedly mechanistically targeted drugs. It varies, though – for depression, it’s a relatively huge effect in clinical trials. For post-surgical bleeding, not so much. For an exercise and lifestyle program, especially if we’re going to be measuring things like mood and outlook, I’d think that placebo effects would be quite meaningful. Blood pressure will show up there, too, and a number of other things that are tied in to cortisol and other stress responses.

And if you can improve those, fine. Just don’t try to convince me, unless you have good evidence, that it needs to be these particular Chinese gestures, because I’ll ask you what would happen if you did all of them in reverse instead (would your blood pressure go up?) And especially don’t try to convince me that the effects are due to fuzzily defined life energies that Iron Age shamans are tuned in to, but which we somehow can’t detect.

Comments (40) + TrackBacks (0) | Category: Snake Oil

January 13, 2009

More on Pfizer's Layoffs

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Posted by Derek

Pfizer's made an announcement about the dimensions of its research cuts - 5 to 8%, which means about 500 to 800 scientists this year. These are (for the most part, I presume) the "not in our current research areas" people from the company's recent re-work of their therapeutic areas.

What I don't know is if they're finally actually telling these people anything. Now, many biologists with a specialization in an abandoned therapeutic area knew instantly that they had to seek a new job when the earlier news came out. But there are plenty of chemists on the block, too. Chemists are sort of vaguely associated with therapeutic areas, as compared with biologists, so that makes it much harder to guess who's going to go.

So, is Pfizer telling anyone today? Or is this just another bizarre chance to whistle the blade over everyone's heads?

Update: yep, it's today, going on right now.

Comments (71) + TrackBacks (0) | Category: Business and Markets

Lack of Experience, You Know

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Posted by Derek

OK, solid chemistry around here today. It looks as if I'll be running a ring-closing metathesis reaction soon. Nobel Prize in 2005, all over the chemistry journals for years. . .and I've never had occasion to use one until now. And when I think about it, there are quite a few other reactions in that category for me.

For example, I'm not at all sure that I've ever done a directed ortho-metalation. I've come close a few times, and I couldn't absolutely swear that I've never done the reaction, but none come to mind. No Fischer indole synthesis for me, because I've always been able to buy the indoles I need, and the same thing applies (fortunately) to the widely disliked Skraup cyclization for quinolines. I've never done an Eschweiler-Clarke reaction, although there have been several times I've needed to form methyl amines, and it probably would have been a good idea.

I've never done any of those multicomponent condensation reactions (Ugi, Passerini, etc.), partly because I've never done much combinatorial chemistry. And I've never done a Rosenmund reduction, but jeez, in this day and age, who has? No Julia olefination, no Fries rearranagements, no Kolbe-Schmitts (or Kolbe anything, come to think of it). And no Paterno-Buchi reactions, because I haven't really done any photochemistry for about twenty years.

I suppose the biggest gaps in my record are the RCM (soon to be filled) and the directed metalation (unless I can think of one that I've blocked from my memory somehow). Most of the other big ones I've done at one point or another, albeit perhaps only once or twice: the last time I ran a Wurtz coupling, on purpose, anyway, was twice in the summer of 1983. I have run a lot of the obscurities as well, of course (Shapiro elimination, anyone?) And I have a lot of fondness for some lesser-known reactions, such as the Prins cyclization, which got me out of a tight spot in my first year of grad school (I've been grateful ever since).

So here's my chem-geek question for the laboratory-bound part of my readership: what famous reactions have you never done? Have you been avoiding it for some reason, or have you just never needed the thing (and wondered why it's so darn famous)? Confess below!

Comments (44) + TrackBacks (0) | Category: Life in the Drug Labs

January 12, 2009

An Alternative Prescription From Chopra, Roy, and Weil

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Posted by Derek

Update: a follow-up post is here, for those who want more on Qi Gong, placebo effects and the like.

Well, we don’t even know who the new FDA commissioner is going to be under the Obama administration, but people are already making their bid for a change in direction. In Friday’s Wall Street Journal, you can find Deepak Chopra, Rustum Roy, and Andrew Weil with an op-ed titled “Alternative Medicine is Mainstream”. I think you can go ahead and silently append “. . .And Deserves Serious Mainstream Funding”.

My hopes for this piece were not high – Deepak Chopra, for one, I consider to be an absolute firehose of nonsense. Both he and Andrew Weil should be whacked with sticks every time they say the word "quantum". But they manage to avoid that one here - the op-ed turns out to be a marbled blend of things that I can agree with and things that make me raise both eyebrows. Its general thrust is:

1. Chronic diseases related to lifestyle (diet, physical habits, etc.) account for a large percentage of health care costs. These could be ameliorated or downright prevented through changes that don’t involve medical procedures.

2. “Integrative medicine” (by which the authors mean, among other things, plant-based diets, yoga, meditation, acupuncture and herbal therapies, have been shown (they claim) to help with such lifestyle changes, and with less expense. The definition of integrative medicine is not provided, nor is the boundary line between it and "regular" (disintegrative?) medicine drawn.

3. Therefore, the incoming administration should make these a big part of the health care system as soon as possible. Did we mention the funding?

Now, I can’t argue with that first point. Cardiovascular disease and Type II diabetes could both be much smaller problems if people in the industrialized nations would just eat less food (and better food) and exercise more. The editorial makes it sound as if no one believes this or has ever heard of such a thing, but come on. No one’s heard anything else for decades. However, it seems equally clear that jawboning people about this issue does not do nearly as much good as one might hope.

Whether “integrative medicine” is any more effective is something that I would very much like to see someone prove. The authors seem to be familiar with a bunch of well-controlled studies that I haven’t heard about, and I invite them to trot out some data. But some of the statements in the op-ed make me think that my cardiovascular health won’t be able to stand it if I hold my breath while waiting for that. For example, we have:

”Chronic pain is one of the major sources of worker’s compensation claims costs, yet studies show that it is often susceptible to acupuncture and Qi Gong. Herbs usually have far fewer side effects than pharmaceuticals”.

Studies show, do they? Is there really a believable study that shows that Qi-freaking-Gong, of all things, is good for chronic pain? Ancient hokum about “energy fields” and “life force” does the trick, does it? My idea of a good trial of Qi Gong would involve one group of patients getting the full hand-waving treatment according to the best practitioners of the art. The other cohort gets random hand motions from a system I will gladly invent on request, and which I will have to be forcibly restrained from naming Don Ki Kong. It’ll be full of talk about holistic energies and connections to the universal flow, don’t you doubt it, and I’ll round up some impressive-looking worthies to administer the laying on of hands. Their passes and taps will be carefully screened by the Qi Gongers beforehand to make sure that none of them, according to their system, have any chance of actually having any effects on the Qi (assuming that any of them can agree). We call that a controlled trial to investigate placebo effects.

And I hardly know where to start with those beneficial herbs. The literature I’ve been reading has been showing that many of the herbal treatments show no effects when they’re looked at closely – St. John’s Wort, Echinacea, and so on. The larger and more well-run the trial, the smaller the effects go, in too many cases. But I have no problem with the idea that plants and plant extracts can have medicinal effects, of course: they’re full of chemicals. My whole career is predicated on the idea that taking chemicals of various sorts can alter one’s health. Where I jump off the parade float is at the nature’s-bounty-of-beneficial-herbs stuff, the idea that things are somehow more benign because they come from natural sources. Vitalism, they used to call that. It’s hooey. Strychnine. Ricin. Come on.

The editorial is full of fountains of happy talk like this one:

Joy, pleasure and freedom are sustainable, deprivation and austerity are not. When you eat a healthier diet, quit smoking, exercise, meditate and have more love in your life, then your brain receives more blood and oxygen, so you think more clearly, have more energy, need less sleep. Your brain may grow so many new neurons that it could get measurably bigger in only a few months. Your face gets more blood flow, so your skin glows more and wrinkles less. Your heart gets more blood flow, so you have more stamina and can even begin to reverse heart disease. Your sexual organs receive more blood flow, so you may become more potent -- similar to the way that circulation-increasing drugs like Viagra work.

Calling Dr. Love! All I have to do is change one letter in my last name, and I'm in business, expanding brains and other useful body parts. Unfortunately, that first sentence typifies a lot of thinking in this area. It's one of those "isn't it pretty to think so" statements. As far as I can see, deprivation and austerity have been the norm for most people throughout most of human history, even though they were eating natural foods and getting lots of exercise and fresh air. And one of the big reasons that people put on weight is that they have the freedom to experience the joy of tasty food a bit too often. No, this is noble-sounding stuff, but there's nothing behind it.

Update: Orac's take, with more on those "studies".

Comments (70) + TrackBacks (0) | Category: Press Coverage | Snake Oil

January 9, 2009

Poor Equipment Revisited

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Posted by Derek

A colleague came by a while ago and said "You know, the comments to that last post of yours are in danger of turning into Monty Python's Four Yorkshiremen sketch". At the moment, things are running about 50/50 between the "lack of equipment teaches you skills" and "lack of equipment wastes your time" camps. . .

Comments (14) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs

The Perils of Poor Equipment

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Posted by Derek

The late Peter Medawar once wrote about resources and funding in research, and pointed out something that he thought did a lot more harm than good: various romantic anecdotes of people making do with ancient equipment, of great discoveries made with castoffs and antiques. While he didn’t deny that these were possible, and admitted that you had to do the best with what you had, he held that (1) this sort of thing was getting harder every year as science advanced, and (2) while it was possible to do good work under these conditions, it surely wasn’t desirable.

His most interesting point was that lack of equipment ends up affecting the way that you think about your research. It’s not like people with insufficient resources sit around all day thinking of experiments that they can’t run and can’t analyze. If you know, in the back of your mind and in your heart, that there’s no way to do certain experiments, then you won’t even think about them. Your brain learns to censor out such things. This limits your ability to work out the consequences of your hypotheses, and could cause you to miss something important.

Imagine, say, that you’re working on some idea that requires you to find very small amounts of different compounds in a final mixture. A good LC/MS machine would seem to be the solution for that, but what if you don’t have access to one? You can spend a lot of time thinking about a workaround, which is mental effort that could (ideally) be better applied elsewhere. And if you had the LC/MS at your disposal, you might be led to start thinking about the fragmentation behavior of your compounds or the like, which could lead you to some new ideas or insights – ones that you wouldn’t have if you’d had to immediately cross off the whole area.

If you’re in a resource-limited situation, then, you’ll probably try to carefully pick out problems that can actually be well addressed with what you have. That’s a good strategy, but it’s not always a possible one. Huge areas of research can be marked off-limits by the lack of key pieces of equipment, and by the time you’ve worked out what’s possible, there may not be anything interesting or important left inside your fence. Medawar’s point was that being stuck inside such a perimeter would not only hurt the way that you did your work, but could eventually do damage to the way that you thought.

It occurs to me that this is similar to George Orwell's claim in "Politics and the English Language" that long exposure to cheap, misleading political rhetoric could damage a person's ability to think clearly. "But if thought corrupts language, language can also corrupt thought". There may be other connections between Orwell's points and scientific thinking. . .definitely a subject for a future post.

In fairness, I should mention that the flip side of this situation isn’t necessarily the best situation, either. Having everything you need at your disposal can make some researchers very productive – and can make others lazy. Everyone has stories of beautifully appointed labs that never seem to turn out anything interesting. There’s danger in that direction, too, but it’s of a different kind. . .

Comments (35) + TrackBacks (0) | Category: Academia (vs. Industry) | Life in the Drug Labs | Who Discovers and Why

January 8, 2009

Short Items: India, Sanjay Gupta, Satori Pharmaceuticals

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Posted by Derek

I have a few short links for everyone today. One series of posts that you might not have seen from Xconomy is a tour of the technological hot spots of India by Boston University's Vinit Nijhawan. It's interesting stuff for people like me who haven't been to the country, and he isn't shy about pointing out both the good and the bad about India's current situation. He's not focusing on the chemistry/pharmaceutical sector, but it's an interesting read in general. I would very much enjoy seeing a similar series written from China - perhaps the Xconomy folks are working on that one?

Next: if Sanjay Gupta really is going to be surgeon general (and why not?), it's worth watching his exchange with Michael Moore when Moore's movie "Sicko" came out. This is a 17-minute YouTube clip, and you may not make it through if you can't stand Michael Moore, but it has some good moments. Gupta is a *lot* more reasonable dealing the Moore than I would have been, but gets hammered on for his pains anyway.

And here's an interesting one, from a financial standpoint. Raising money for startup companies has, in the last few months, gone from the usual state of “not so easy” to “nearly impossible”. Everyone’s hoping for that to improve, but for now, this is a nasty time to try to float a new startup. That goes for follow-on financing, too, naturally, and that can hurt even more than troubles with start-up money. You can potentially delay the launch of your new venture – after all, no one else is getting anything off the ground, either – but if you’re already got a company going, the funds need to keep flowing. Companies that lined up more money in the middle of 2007 are shivering over the narrowness of their escape.

So it's impressive that an outfit called Satori Pharmaceuticals has made it through a full round of venture funding, and for Alzheimer's therapies, no less. That's a notorious graveyard for good ideas, but (at the same time) it's equally notorious for being hugely under-served. Good luck to them - they'll need it (and don't we all?)

Comments (20) + TrackBacks (0) | Category: Alzheimer's Disease | Current Events | Press Coverage

January 7, 2009

Things I Won't Work With: Azidotetrazolate Salts

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Posted by Derek

An early favorite has appeared in my “most alarming chemical papers” file for this year. Thomas Klapoetke and Joerg Stierstorfer from Munich have published one with a simple title that might not sound unusual to people outside the field, but has made every chemist I’ve shown it to point like a bird dog: “The CN7 Anion”. The reason that one gets our attention is that compounds with lots of nitrogens in them – more specifically, compounds with a high percentage of nitrogen by weight – are a spirited bunch. They hear the distant call of the wild, and they know that with just one leap of the fence they can fly free as molecules of nitrogen gas. And that’s never an orderly process. If my presumably distant cousin Nick Lowe does indeed love the sound of breaking glass, then these are his kinds of compounds. A more accurate song title for these latest creations would be “I Love the Sound Of Shrapnel Bouncing Off My Welder’s Mask”, but that sort of breaks up the rhythm.

These Bavarian rowdies have prepared a series of salts of the unnerving azidotetrazolate anion. As they point out, the anion was described back in 1939 (in what I hope was a coincidental association with the outbreak of the Second World War), but its salts are “rarely described in the literature”. Yes indeed! People rarely spray hungry mountain lions with Worcestershire sauce, either, come to think of it.

After reading this paper, I’m considering taking my chances with the mountain lions. The authors report a whole series of salts, X-ray structures and all, which range from the “relatively stable” lithium and sodium derivatives all the way to things that couldn’t even be isolated. In the latter category is the rubidium salt, which they tried to prepare several times. In every case, the solution detonated spontaneously on standing. And by “spontaneously”, they mean “while standing undisturbed in the dark”, so there’s really just no way to deal with this stuff. It’s probably a good thing they didn’t get crystals, because someone would have tried to isolate the hideous things. The cesium salt actually did give a few crystals, which they managed to pluck from the top of the solution and get X-ray data on. A few hours later the remaining batch suddenly exploded, though, which certainly must have been food for thought.

The authors went on to investigate the thermal behavior of these wonderful compounds, another risky move. As it turns out, they have calorimetry data on only five of the salts, because when they got to the sodium derivative, “a violent explosion destroyed the setup”. They also did sensitivity tests, using a standard drophammer rig from the Bundesanstalt fuer Materialforschung, evocatively abbreviated as BAM. These, along with the friction and spark tests, put these compounds well into the “primary explosive” category. Well, the ones that they could get data on, that is: the potassium and cesium compounds blew up as they tried to get them into the testing apparatus. So it’s safe to assume that they’re a bit touchy, too.

One of my favorite parts of the paper is the mention (found in much of the recent high-energy materials literature) that high-nitrogen compounds are worth investigated as “green” explosives, which makes me think that the whole environmental-rationale business must be reaching its end points. The notion of a more environmentally friendly way to blow things up aside, I have to salute the paper’s authors. They’ve made compounds that no one will have to make again, and survived the experience. Read the paper and be glad that this wasn’t your PhD project. . .

Comments (42) + TrackBacks (0) | Category: Things I Won't Work With

New Chemistry

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Posted by Derek

So I see that Nature Chemistry looks to be fueling up to launch. I’m curious to see how that one will do. The other Nature journals have done pretty well at preserving the prestige of the name, but I hope that they haven’t reached the point of diminishing returns just when they get to my specialty.

And this will be unusual, since you don’t see many attempts to launch a high-end journal from scratch. Most new journals aim for the middle (or worse), figuring that that’s where the papers will come from. But Nature Chemistry will presumably try to compete with JACS and Angewandte Chemie. My guess is that they’ll be able to do that, which means that the journals one tier down will be the ones that feel the consequences. On the other hand, it’s not like Nature has a reputation for paying much attention to chemistry over the years, so perhaps the cachet won’t carry over in the same way that it did for, say, Nature Medicine. We shall see. . .

Comments (2) + TrackBacks (0) | Category: The Scientific Literature

January 6, 2009

Why Pfizer?

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Posted by Derek

I get occasional comments and e-mails asking why I’m so hard on Pfizer. It’s not that I have anything personal against the company – I’ve never worked there, and they’ve never turned me down for a job. And I have a lot of friends there as well - the company has a lot of good people working for it. No, it’s not Pfizer so much as the way that Pfizer exemplifies for me a lot of things that I think have gone wrong with the industry.

First, of course, is sheer size. As I’ve said numerous times, I think that many things scale as a drug company gets larger, but research productivity isn’t one of them. If anything, it may go in the other direction. Pfizer is an excellent example of just what I’m talking about. If there were any reliable correlation of size to internal research success, this is where you’d expect to see it. But Pfizer has been notoriously unproductive in its own labs. Some of that has been sheer bad luck, but you can’t use that explanation to cover the whole problem.

Put simply, I think that really huge drug companies are a bad thing. A collection of smaller ones carved out of the same resources would probably explore more therapeutic avenues, and in a more nimble and focused manner. I also like competition in this business, because it keeps us moving, and because it leads to a wider variety of approaches being tried out for each problem. Mergers and buyouts have, I feel sure, not been good for the ecology of the industry, and Pfizer is the absolute champion of that style. Large and productive research organizations have disappeared beneath the waves because they had the misfortune of discovering something that Pfizer wanted to buy.

And there’s also the triumph of marketing. That’s one area where Pfizer really excels, but the problem with being a marketing powerhouse is that you might end up thinking that you can sell almost anything. The company’s disastrous experience with Exubera (the inhaled insulin product that missed its sales targets by, what, 98 per cent?) is a sobering example. If you start believing your own press releases, you might convince yourself that you’re going to sell a billion dollars of Exubera, and at a huge company you’ve got the money and the resources to pursue that dream right over the cliff. Groupthink finds a bigger arena in which to work its magic.

So there it is. Other companies have similar problems, but when you go to Pfizer, you find them all together, in concentrated form. So when they announce that they’re going to go out and buy someone else to work their way out of their (massive) coming troubles, it makes me wince. It just seems like the opposite of what we need.

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

Pharmalot Is No More

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Posted by Derek

I noted with sadness yesterday that Ed Silverman has packed in the Pharmalot blog. He did an excellent job there, picking up a lot of industry news from all over. Most of it was in the “Trouble for Company X” vein, but that’s to be expected. Ed’s a good reporter, and “Things Going Fine Over at Company X” is not much of a story. If this item is correct, though, we’ll be seeing more of him, which I’m glad to hear. The newspaper business is in even worse shape than the drug industry, so I’m glad to see it when someone there lands safely. (People still need pharmaceuticals; they’re not so sure if they need newspapers so much).

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January 5, 2009

Well, Hose Me Down. . .

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Posted by Derek

Pfizer's Jeff Kindler says that the company: "is willing to acquire a large rival drug company to improve its financial health".

In other news, bears have expressed a willingness to defecate in forested areas.

Comments (20) + TrackBacks (0) | Category: Current Events

New Year - I Hope!

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Posted by Derek

In past years, around this time I’ve often done a look back at the previous year in the drug industry. I hope that no one will be disappointed if I scuttle that tradition, because honestly, I have no desire whatsoever to relive what drug research went through in 2008. It may have been the toughest year for industry scientists in the modern era – everyone I know struggles to find a comparison.

I’d rather spend my energies on 2009. Let’s just stipulate that 2008 was, on balance, horrendous: what does that tell us? How did we end up in this position, and how can we avoid more of the same? There’s a lot of arguing room in those questions, but I think that we can agree that the proximate cause is that we’re not coming up with enough good drugs. 2008, for all its ugliness, was a handful of good products away from being a decent year. Why were we short that handful?

You have to go back some years to answer a question like that, given the industry’s lead time. The projects that were begun in the mid-to-late 1990s are clearly not coming through in the way that everyone had hoped. Is it that our attrition rate has gone up, or have we just not taken enough things to the clinic, or some of each?

Let’s think about that first problem, which certainly seems to be real enough. Is it that the easy targets have all been worked over, leaving us with only the tough ones? I don’t think that’s the whole explanation, although that’s certainly part of it. Still, even some of the big drugs from years past wouldn’t have made it through our current structures. So are the hurdles set too high during development – that is, do we know too much about potential problems, without having learned a corresponding amount about how to fix them? That’s got to be a big factor, which leads to a New Year’s resolution: try to spend as much time fixing problems as finding them. That’s a hard one to live up to, but it’s a goal to work toward.

And if we’re going to talk about that latter number, we’re going to have to cut through the often artificial “projects advanced” figures that circulate inside companies. Anyone who’s been around this business has seen some long shots (and some outright losers) officially pushed forward just to make some year-end target. Now, long shots are fine. To a good approximation, everything we do is a long shot. And everything has to go to the clinic eventually (or die) – but we have to make sure that we’re not just checking boxes. So that’s another resolution: spend less time kidding ourselves.

Of course, there’s a flip side to the number of compounds going to the clinic. Could it be that we’re being too cautious, because we have too many potential worries (those high hurdles mentioned above)? Should we be taking more things forward? Well, that’s an expensive proposition, the way things are set up now. So here’s another hard-to-live-up-to resolution: find ways to go to the clinic without betting our shirts every time. That’s been a big focus the last few years (biomarkers, etc.), but we need every idea and technique we can think of (microdosing? Simulations, even?). The cost of getting answers in humans is getting too high for us to try out as many ideas as we need to.

And here's a less macro-scale resolution, which I plan to start putting into practice immediately: don't let fear run your research. Try some things that you aren't sure about. Take some chances. Put down some bets. I've got several that I've let sit in the should-I-do-this limbo for too long, and I'm going to do something about that. Join me?

Comments (12) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Drug Industry History | Who Discovers and Why