Back in May of this year, I wrote that:

. . .Everyone keeps mentioning that "China isn't as cheap as it used to be". And that's going to continue, I think - I'm not expecting them to reach US/EU cost levels any time soon, but the bottom-line advantages of doing contract work there, which a few years ago were immediately apparent, are starting to become more of a matter for thought. . .

I went on to wonder if some of the big investments in China might turn out to come on line about the time the cost advantages disappeared. Well, it's happening right on schedule. Via FiercePharma, we have this piece from Life Science Leader:

A 30% to 50% cost savings was the main driver for sourcing starting materials, intermediates, APIs, and (to some extent) finished drugs. Cheaper labor, tax advantages, undervalued currency and lower capital, and overhead costs all contributed to this. All of these advantages are expected to erode in the coming years as inflation in China rises, currency appreciates, and tax rebate structures start to evolve. . .

. . .With these changes China’s current gross cost advantage of 30% to 50% could easily go down to 13% to 25%. Factor in supply chain complexity (lead times and inventory implications), rising costs of quality assurance, and upcoming stringent environmental regulations, and Western pharmaceutical companies will start to rethink their China outsourcing strategies. Accommodating for these factors, the net cost advantage for some pharmaceutical firms could easily vanish.

This does not mean, of course, that pharma outsourcing is going away. It's just going to keep moving to the cheapest suppliers that can deliver the goods. India may well pick up some of this business (although their costs will be increasing as their wages rise), and other countries could well move into this space. (Thailand? The Philippines?) And then their costs will gradually grow, as they get richer, and someone else can move in. No, no one gets to sit back, set things on automatic pilot, and watch the money roll in, which is how it should be.

Nature Reviews Drug Discovery has an article on behavior in large drug organizations, which they put together after interviewing a long list of current and former R&D heads. Many of the recommendations are non-startling (find ways to reward people who are willing to take calculated risks, encourage independent thinking, all those things that are easy to write down and hard to implement). One part near the end caught my eye, though:

Companies should examine what we term the 'columns outside the doors' phenomenon and the subtle impact that this form of recognition might have on entrepreneurial behaviour. Smith described this phenomenon, which occurs across the world: as start-up companies become successful, they are relocated from humble laboratories to grander buildings with columns outside their doors. Interestingly, such edifices often violate the observed inverse square relationship between communication among scientists in laboratories and the distance between these laboratories. We offer this insight more as a provocative thought than as a firm recommendation.

And what what reminded me of was a very similar observation by C. Northcote Parkinson, of Parkinson's Law fame:

The outer door, in bronze and glass, is placed centrally in a symmetrical facade. Polished shoes glide quietly over shining rubber to the glittering and silent elevator. The overpoweringly cultured receptionist will murmur with carmine lips into an ice-blue receiver. She will wave you into a chromium armchair, consoling you with a dazzling smile for any slight but inevitable delay. Looking up from a glossy magazine, you will observe how the wide corridors radiate toward departments A, B, and C. From behind closed doors will come the subdued noise of an ordered activity. A minute later and you are ankle deep in the director’s carpet, plodding sturdily toward his distant, tidy desk. Hypnotized by the chief’s unwavering stare, cowed by the Matisse hung upon his wall, you will feel that you have found real efficiency at last.

In point of fact you will have discovered nothing of the kind. It is now known that a perfection of planned layout is achieved only by institutions on the point of collapse. . .

It is by no means certain that an influential reader of this chapter could prolong the life of a dying institution merely by depriving it of its streamlined headquarters. What he can do, however, with more confidence, is to prevent any organization strangling itself at birth. Examples abound of new institutions coming into existence with a full establishment of deputy directors, consultants and executives; all these coming together in a building specially designed for their purpose. And experience proves that such an institution will die. . .

Readers may have a few examples in mind from the drug industry. (The freshly constructed labs at Sterling, for example, completed around the time that Kodak was wiping the place out, are well spoken of). So, those of you in temporary quarters, jammed into buildings that don't quite work, may not be as bad off as you might think.

Science (and blogging) will march along without me today, in honor of Labor Day in the US. I hope it doesn't get too far out ahead, so I can catch up.

I'm home preparing for a big dinner of some of my native Arkansas food (catfish and hushpuppies), planting flower bulbs, and teaching my two children to play seven-card stud high-low poker. Busy, busy, busy.

It's always good to hear about an older compound that may be doing good things that we didn't realize. The current example is metformin, the diabetes drug known to many by its brand name Glucophage, but a generic compound for some years now. Evidence has recently been accumulating that patients taking it over the long term may well have lower incidence of several types of cancer, which is a refreshing change from the usual creeping realizations in this business. (There's a reason for that - the opportunities to mess something up inside a cell, something you probably didn't even know was there, are far, far, more numerous than the opportunities to make something work the way you want).

A new paper may well have tracked down a mechanism for this effect, which adds to the sense that it's real. Here's a summary of the work - it looks like an mTOR-driven process, which is plausible. Specifically, it seems to inhibit the TORC1 pathway, though at least two different mechanisms. That's an important player in nutrient sensing and cellular growth, among a bewildering variety of other things, and the whole mTOR area has been the subject of oncology research for quite a long time now.

Metformin (and related biguanides) might be acting on it in a very useful way. Mice exposed to a known lung-cancer agent were substantially protected by pretreatment with the drug. What's not clear yet is if that direct TORC1 effect is the reason, or if it's a more general downstream effect having to do with metformin's effects on glucose levels and insulin signaling. If it's the latter, there are tumor lines that should (unfortunately) be able to evade the problem, specifically ones that have their PI3K signaling cranked up already, so it's going to be quite interesting to see how metformin does protecting against those. As has been noted many times, nutrient sensing, insulin signaling pathways, carcinogenesis, and mechanisms of aging are tangled together in ways that it's very much in our interest to unravel. (mTOR specifically is right in the middle of it, apparently).

These results (both the new mechanistic study in mice and the retrospective clinical observations) would seem to strongly suggest trying metformin out in patients with a high risk of developing various sorts of cancer. It also suggests that, other things being equal, Type II diabetics might want to use metformin to take advantage of its apparent side benefits. A protective effect would be very welcome news indeed - it's terribly difficult to do anything about most tumors once they've occurred, and the best thing would be for them not to appear in the first place.

Oh, and one more thing. If everyone had followed Sidney Wolfe's advice when metformin first came out - not to use it - we wouldn't have found out about these effects at all. Would we?

Blogging time is short today, since I'm on a deadline to produce a couple of posters for presentation. These are for an internal hoe-down, unfortunately, so I won't be able to share the fruits of my labors with everyone out there in the readership. With any luck, though, they'll turn into public presentations/publications eventually, though.

As far as I'm concerned, posters are quite a bit harder to work up than a talk. They really should stand by themselves, for one thing, so you can't fill in any holes verbally. And narrative flow is harder: there's no chance to go back and re-emphasize or contrast with later slides, because the whole thing is sitting out there, with no guarantee of what order people will use to see its parts. (I find that narrative is one of my main weapons in a presentation, so going without it is always tough).

I care about design, too, probably more than I should, so a poster also presents complications there. If visual cues wander a bit from slide to slide through a presentation, that's not good, but it's not fatal, either. But when everything's up there on one sheet, the messages really have to be consistent: same fonts, same colors, same rotations, views, and angles, etc.

But at these times I try to remind myself of what happened to a friend of mine many years ago. She was working on a poster for an ACS meeting, and took it to her PI to look over. "Yes, yes, that looks good", came the word, "but could you perhaps take this part over to here? And emphasize this a bit more? And. . ." So she went back and made the changes, and took the poster back for a re-check. "Much better! Yes. . .but I wonder if maybe this part should be bigger? And did you find a way to include those results where. . ." Back for another round.

After another iteration of this, she caught on. She started taking an unchanged version back to the PI, and after another couple of rounds of seeing the exact same poster, it was finally pronounced ready for viewing. Saves time, saves effort - try it when you can!

Over at BoingBoing, they're investigating the question: "How long would your PhD have taken if everything worked the first time?" I have to admit, it took me a few minutes to adjust my head to that idea, since God knows, nothing in my PhD ever looked like working the first time.

And it's a hard one to answer, because I had to do some backtracking, as so often happens in total synthesis. This was of the "Dang it all, turns out I can't install that carbon at that step, so I'm going to have to go back, put it in earlier, and hope the downstream stuff still works" variety. (Not all of it did, of course). So how do you account for tactical moves like that? There are several layers.

How long would it have taken if I'd chosen the right move each time, and each reaction worked on the first shot? Even then, that's a tricky one, because one typically runs things on a test scale and then on larger amounts as the ground firms up beneath you. So if things had worked every time, just fine, and I'd scaled up as soon as they did each time. . I'd say around a year. Maybe even nine months; it's hard to say, because the concept of everything working is so alien.

Then one could ask, how long would it take to run through the chemistry in your dissertation, straight through, knowing what there is to know about it? In that case, it would be shorter. Just flogging away at the procedures, nonstop, and having nothing go wrong along the way (hah!), I think you could beat through everything in mine in two or three months. Boy howdy, would I hate doing that.

What does that leave out, then, of a degree that took me four and a half years? (A flippin' short span, I might add, considering some of the other degrees coming out of my old group). Well, there are all those false starts down synthetic routes that ended up painting me into corners. Being carbohydrate-based synthesis, many of those were protecting group problems, but there were a couple of rip-the-whole-sequence-up episodes, too, when things just wouldn't go any further. And there were things like finding out that a base camp of material I'd stored in the freezer had gone to hell anyway, in the dark, under argon. And realizing that a TBDMS group had up and migrated on me, such annoyances as that, which also involve proving that it happened and making sure that I knew where everything was still attached.

And there's an awful lot of time spent just getting each reaction to work - six or eight or ten ways to bring in a methyl group. Four or five different reduction conditions. All those choices, every time: borane THF or borane-dimethylsulfide? Swern or PCC? Hydrogenation catalysts, Lewis acids, finding out that switching from BuLi to KHMDS when making methylene Wittig reagent changed the yield of alkene from 10% to 90%. Chip, chip, chip, at every step along the way. At the time, it seemed as if my legs were mired in not-so-fresh concrete, three feet deep across the lab. Looking back, though, I think I must have been flying. . .

Chad Orzel has a post up on the two halves of physics, and about how people tend to forget one of them: the experimentalists. I think he's right, and the problem is the glamorous coating that began to stick to theoretical physics in the early 20th century (and has never completely flaked away).

Several things led to that split: the startling predictions of relativity and quantum mechanics, borne out by experimentalists right down to the most unlikely-sounding results, for one. The Manhattan Project, which was a triumph of engineering, but was seen, I'd say, by many in the general public as sheer theory somehow made real. The personal fame of people like Einstein, and the fame of later practitioners like Feynman and Hawking. All of this made experimental physicists seem either like 19th-century relics, or (more often) made them confused in the public's mind with theorists from the very beginning. (The only post-1900 physicist that I can think of who was both a great theorist and a great experimentalist was Enrico Fermi). Update - qualified that to take care of off-the-charts figures like Isaac Newton.

Chemistry, on the other hand, has always been an experimental science in the public mind. Say "chemist", and people think of someone in a lab coat, in a lab, surrounded by chemicals. "Theoretical chemistry" is not a phrase with any popular currency, as opposed to "theoretical physics". Even many chemists tend to think of someone who spends all their time on theory as being close to a physicist, or even a mathematician.

Some of the practitioners don't do much to clarify matters. Witness the great Lars Onsager, who really was a chemist (and won the 1968 Nobel for it). But his PhD dissertation, which had to be whipped up when Yale discovered he didn't have a doctorate, was (disconcertingly) on Mathieu functions, and Yale's math department said that they'd be glad to grant him the degree if the chemists had any problem with it. Very few people are competent to read all of Onsager's Collected Works.

I agree with Orzel, though, that experiment is the beating pulse of any scientific field. That's the worry that some people have had about physics in recent years, that it's strayed into areas where experiments cannot help. Chemistry will, I think, never have that problem. But we've got others.

Here's a lab question for everyone. I have a bottle of Aldrich copper oxide nanopowder on my lab bench; I've been meaning to try it out for some Ullmann reactions. I note that Aldrich (and others) are now selling a variety of such nanopowders, mostly metals and insoluble metal compounds.

And that makes sense, because these are the things that tend to react at their surfaces, and you'd have to think that a real nanopowder would have a tremendous surface area. My question is: does this really work out? Has anyone noticed a difference between the nanopowder form of a particular reagent and its more traditional one? I can imagine there being one - but I can also imagine the particles clumping up under some conditions and giving you back the equivalent of the cheaper stuff, too. Any hands-on experience out there?

Here's an excellent roundup of the Avastin story, referenced in an earlier post here.

I have to say, I've been disappointed in some of the commentary on this issue (which that article goes into as well). Too many people have jumped right to the conclusion that yep, here's what the new health care plan is going to do to us, yank life-saving medicines out of our hands because they cost too much. Well, I think that the health care bill was a disastrous idea, myself, and at the same time I still think that Avastin doesn't deserve approval for metastatic breast cancer.

The best evidence we have is that Avastin doesn't help these patients and may well even hurt them. That would be true even if it were free. And remember, off-label use is still perfectly legal. Anyone who wishes to spend their own money on something that does not appear to work - and that Wall Street Journal editorial aside, Avastin really doesn't, here - is free to do so. Getting everyone else to pay for it is quite another thing, and you'd think that conservatives and libertarians would find that argument more appealing than they seem to.

The FDA meets to discuss this issue on September 17. I wish everyone who's gearing up to write editorials about the decision would get up to speed on the facts before then.

A Swiss newspaper reported over the weekend that Roche is planning large cuts, across much of their multinational organization. Here's the original article, for those of you who read German.

Looking it over, it seems to depend on the word of one Roche insider - or, more accurately, someone the newspaper describes as having the "best contacts" there. This person says that a decision will be made this week on cuts in research and other parts of the organization, and that Roche has been trying for some time to work out a large cost-cutting program.

The company denies any specific plans, but makes the appropriate noises about always looking for ways to do things more efficiently. Anyone heard anything else?

Well, so much for my fantasy of Sanofi-Aventis walking away from their attempt to buy Genzyme. They went public yesterday with a $69/share offer - even lower than most people were thinking - and just a little while ago, Genzyme publicly turned them down.

What's more, this is apparently the same price at which Genzyme (privately) balked earlier in the summer. The big difference now, of course, is that the dollar figures are out in the newspapers. And the only reason to do it that way, at least as far as I can figure, is if you're going to try to wage a hearts-and-minds battle for Genzyme's shareholders: a hostile offer, or at least the credible threat of one.

I'm in no position to say how well that'll work out. Sanofi-Aventis has, presumably, been sounding out the larger institutional investors to see if they can get something going, while Genzyme has surely been telling them to stick with the current management for a better deal. The big issue is the uncertainty about when the company is going to get its manufacturing problems taken care of. No doubt that's going to be one of the selling points for a hostile bid: "Do you really want to stick with the people who let this happen? And do you really trust them to get it cleaned up when they say that they will?" But that same uncertainly clouds the pricing of the hostile offer itself. Thus. . .$69/share.

If I had to guess, I'd say that the two sides, after a lot of fist-waving, will reach some sort of face-saving figure in the mid-70s. Will the guy that sold all those October $75 calls make out or not?

Time to update the blogroll! Welcome to Liberal Arts Chemistry, "Generally Chemistry, Organic Chemistry - Education and Industry, Junior Prof, C&E News' The Haystack, Just Another Electron Pusher, The Chemical Notebook, and the newly relocated Terra Sigilatta. Then there's the return of Propter Doc and ChemBark.

You always had to wonder how the move of appointing Sidney Wolfe to the Drugs Safety and Risks Management Committee at the FDA was going to work out. The signs of friction are appearing. I'm with the InVivo Blog: this is the first time I've heard of an FDA committee cutting off the microphone on one of its own members. And you'd think that everyone involved would be able to manage things so that didn't happen - wouldn't you?

Chemjobber has a post up on the responsibility of the professor in the Texas Tech explosion case. I have to agree with him: if you're going to get grant money to have your group work on energetic materials, you have to keep a close eye on things. And the C&E News piece on the whole affair doesn't make it sound like that was happening. It's easy for me to sit here, ex post facto, and say something like this, but I'll say it anyway: from what I can see, this research group wasn't being run the way it should be.

At the same time, there's no amount of training that will keep a real idiot from doing something stupid (thus the German quote that led off my previous post on the subject). Believers in seminars and checkboxes always have to come up against that fact, and against the people that exemplify it. But here's what you have to do with such people: get rid of them. Get them off the dangerous projects at the very least, and try to get them out of your group, out of the building, out of chemistry as a career. Anyone who would scale up a known sensitive, energetic material by a factor of 100 over the recommended amount and then put it in a mortar and pestle does not belong in a chemistry lab.

But that takes us back around to the professor again. Anyone running a research group should know when there's someone in it with a reputation as a wild-eyed cowboy. And when your group is concentrating on hazardous materials, well. . .

So sure, there should have been more training, and it sure sounds as if this lab could have used a better culture in general. But the first thing it could have used was this guy's rear end being kicked down the stairs. And Chemjobber's right: all of these are the responsibility of the PI.

Here's a roundup of the latest reports on the potential Genzyme takeover. For one thing, it looks as if people on the inside are talking again, after a good period of silence. And for another, it looks as if Sanofi is applying the pressure: no deal above $70/share.

Either Genzyme's board agrees to entertain such an offer, or they get to explain to the shareholders why they think it's just too low. Sanofi-Aventis, for its part, may well be actually thinking about walking away, which is a move that I'd applaud. Not only do I not like most big mergers in this business, I've also never liked the way these deals take on a momentum of their own. Going through with some transaction because, well, we've started doing it and now things are just sort of rolling along, y'know, is a terrible idea. It's the sort of reasoning that vacuum cleaner salesmen and used-car dealers try to encourage. Oh, and big impressive investment banks, too.

The Vinca alkaloids are some of the most famous chemotherapy drugs around - vincristine and vinblastine, the two most widely used, are probably shown in every single introduction to natural products chemistry that's been written in the past fifty years. But making them synthetically is a bear, and extracting them from the plant is a low-yielding pain.

A new paper in PNAS shows that there's still a lot that we don't know about these compounds. What has been known for a long time is that they're derived from two precursor alkaloids, vindoline and catharanthine. This new work shows that the plants deliberately keep those two compounds separated from each other, which helps account for the low yield of the final compounds.

As it turns out, if you dip the leaves in chloroform, which dissolves the waxy coating from the surface, you find that basically all the catharanthine is found there. At the same time, even soaking the leaves in chloroform for as long as an hour hardly extracts any vindoline - it's sequestered away inside the cells of the leaves. The enzymes responsible for biosynthesis are probably also in different locations (or cell types), and there are unknown transport mechanisms involved as well. This is the first time anyone's found such a secreted alkaloid mechanism.

Why does Vinca go to all the trouble? For one thing, catharanthine is a defense against insect pests, and it also seems to inhibit attack by fungal spores. And what the vindoline is doing, I'm not sure - but the plant probably has a good reason to keep it away from the cantharanthine, because producing too much vincristine, vinblastine, etc. would probably kill off its dividing cells, the same way it works in chemotherapy.

The authors suggest that people should start looking around to see if other plants have similar secretion mechanisms. And this makes me wonder if this could be a way to harvest natural products - do the plants survive after having their leaves dipped in solvent? If they do, do they then re-secrete more natural waxes to catch up? I'm imagining a line of plants, growing in pots on some sort of conveyor line, flipping upside down for a quick wash-and-shake through a trough of chloroform, and heading back into the greenhouse. . .but then, I have a vivid imagination. . .

OK, time (finally) for the latest chapter in the GSK-Sirtris saga. (This is going to get fairly geeky, so feel free to skip ahead if you're not into enzymology). You'll recall from previous installments that Amgen and Pfizer, among others, had disputed whether the reported sirtuin compounds worked the way that had originally been reported. GSK has now published a paper in the Journal of Biological Chemistry to address those questions. How well does this clear things up? Let's take things in order:

Claim 1: Resveratrol is not a direct activator of SIRT1 activity (Amgen). Building on two 2005 papers, the Amgen team said that resveratrol, the prototype SIRT1 ligand, only works in that manner when the fluorescent peptide (Fluor de Lys) was used in the assay. This is due, they found, exclusively to the fluorophore on the peptide - it's an artifact of the assay conditions. Without it, no activation was seen with protein assays in vitro, nor in cell assays. Native substrates (p53-derived peptide and PGC-1alpha) show nothing.

GSK's response: This is true. They too, found that activation of SIRT1 depends on the structure of the substrate. Without the fluorescent label, no activation is seen.

Claim 2: Not only is this true for resveratrol, it's true for SRT1720, SRT2183, and SRT 1460 (Pfizer). The Pfizer team did a similar breakdown of the assay conditions, and found (through several biophysical methods) that the fluorophore is indeed the crucial element in the activity seen in these assays. And again, since that's an artificial tag, the Fluor de Lys-based assays can have nothing to do with real in vivo activity. Native substrates (p53-derived peptide, full-length p53, and acetyl CoA synthase 1) show nothing.

GSK's response: As above, activation of SIRT1 depends on the structure of the substrate. Without the fluorescent label, no activation is seen. SRT1460 and SRT1720 do indeed bind to the fluorescent peptide, but not to the unlabeled versions. Looking over a broader range of structures, some of them interact with the fluorophore, and some don't. There's no correlation between this affinity and a compound's ability to activate SIRT1.

A screen of 5,000 compounds in this class turned up three that actually do work with nonfluorescent peptide substrates (compounds 22, 23, and 24 in the paper). None of these have been previously disclosed. They, however, that even these still don't work when the peptide substrate lacks both the fluorescent tag and a biotin tag.

What's more, when these three compounds are tested on a p53-derived 20-mer peptide substrate, they actually inhibit acetylation, instead of enhancing it. Looking closer at a range of peptide substrates, SRT1460 and other compounds can also inhibit or enhance acetylation, depending on what peptide is being used. An allosteric mechanism could explain these results. It seems more likely that there are at least two specific sites on SIRT1 that can bind these compounds - the active site and an allosteric one. Thus there are several species in equilibrium, depending on whether these sites have substrate or small molecule bound to them, and on how this binding stabilizes or destabilizes particular pathways. In the real cell, this may all be part of various protein-protein interactions.

Claim 3: SRT1720 does not lower glucose in a high-fat-fed mouse model (Pfizer). Even though exposure of the drug was as reported previously, they saw no evidence (at 30 mg/kilo) of glucose lowering or of any increased mitochondrial function. These animals showed increased food intake and weight gain. The 100 mpk dose was not well tolerated, and killed some animals.

GSK's response: not addressed in this paper. It's an enzymology study only.

Claim 4: Resveratrol, SRT 1460, SRT1720, and SRT2183 are not selective (Pfizer). A screen of over 100 targets showed all of these compounds hitting multiple targets, with resvertrol itself showing the closest thing to a clean profile. None of them, say the Pfizer team, are suitable pharmacological tools.

GSK's response: not addressed in this paper. None of the newly disclosed compounds have selectivity data of this sort attached to them, either. I'd be very curious to know how they look, and I'd be very leery of attaching much importance to their behavior in living systems until that's been done.

The take-home: On the enzymology level, this new paper seems to be solid work. But it's the sort of solid work that should have been done around the time that GSK bought Sirtris, and not something appearing in 2010 in response to major attacks in the literature. The first main claim of those attacking papers is, in fact, absolutely true: the original Fluor de Lys assay is worthless for characterizing these compounds. What we learn from this paper is that the assay is worthless for even more complicated reasons than originally thought, and that the whole series of SRT compounds behaves in ways that were not apparent from the published work, to put it lightly.

As to the selectivity and in vivo effects of these compounds, Pfizer's gauntlet is still thrown down right where they left it. The fact that these compounds are so much harder to understand than was originally thought, even in well-controlled enzyme assays, makes me wonder how easy it will be to figure out the rest of the story. . .

Emily Yoffe at Slate has a very accurate piece up on just how hard it is to make progress against things like Alzheimer's, Parkinson's, and other neurodegenerative diseases. The contrast with the hopes of patients - and the hype often surrounding the initial discoveries - is painful.

And we're back to that optimism/realism tightrope. On the one hand, I don't see any reason why we shouldn't be able - eventually - to stop such conditions in their tracks, or to keep them from starting in the first place. (Reversing the damage once it's done, though, is much more of a stretch, to me). But on the other hand - sheesh, we really, really have a lot to learn about these things. The likelihood of any one discovery being the key breakthrough is small - nonzero, but small. So in the long term, I'm an optimist, but in the short term, well. . .every little bit helps, and most of the bits are going to be little.

That's not the sort of news you want to give to someone suffering from these conditions, of course. That desire for encouraging news, along with plenty of other good intentions (and a few not-so-good-ones) leads to the cycles of hype that we've seen over and over. Stem cell research is a perfect example. There really are huge possibilities there, extraordinary ones. But our level of ignorance is also extraordinary. And to go out and make claims that we're going to be able to cure X and reverse Y soon, based on our present knowledge, is just plain irresponsible.

But plenty of people do just that - politicians, headline writers, and others. And then people who only know what they see in the news wonder where things went wrong, and how come these wonderful cures haven't arrived yet. It all makes explaining the real situation that much harder.

It's not like the real situation is even all that terrible. As I said above, I really do think that these diseases - and many others - are eventually going to be treatable. No one likes that word "eventually", though.

If you haven't heard about the explosion at Texas Tech earlier this year, this piece is the place to learn about it. (More from Chemjobber and the newly re-blogging Paul Bracher). In short, two graduate students were preparing a nickel hydrazine perchlorate complex, on far more than the recommended scale, and one of them was severely injured while trying to break up the substance in a mortar and pestle.

This is, as any experienced chemist could tell you, not a surprise. Call me when something like that doesn't blow up. But these weren't experience chemists. They were grad students, and I'm just glad that they didn't pay an even higher price for not realizing what they were getting themselves into.

At the same time, I find myself lining up more with Bracher's post, although I won't express myself quite as vigorously. The entire point of this research program was to look at hazardous energetic materials. The professor involved specifically told the students not to make more than 100 mg of material; they made ten grams. The injured student then ground up this material - yep, I did say "mortar and pestle" for real back there - with no blast shield, and gave the stuff one last poke after having taken off his goggles. He now gets to learn to write with his other hand. I can't figure out how he's still alive.

It's cruel, but one thing I actually respect about the physical sciences is that they have no regard for humanity. No exceptions are made; they respect no laws save their own. In a chemistry lab, we are dealing with the world as it really is, not as we'd like it to be. And if you want to believe that you can scale up the synthesis of a violent explosive by a factor of 100, despite warnings, and poke at the material without protection - well, you'd be just as well off doing it to a tiger. Perchlorates don't care what you think you can get away with, or how invulnerable you think you are.

The long-delayed PNAS paper on the chronic fatigue/XMRV results has finally come out. It's not going to stop the arguing.

From what I can see, this team didn't find "canonical" XMRV in the samples from CFS patients. But what they did find was a whole slew of similar-looking traces of murine leukemia viruses (MLVs). (The samples do not appear to have been contaminated, which is the first thing you'd wonder about).

So now we're back to more head-scratching. Is XMRV a culprit at all, or is it some other related MLV? Or is it, instead, several of them at the same time? How many people without symptoms show the same MLV signs anyway? And so on. It's clear that this story is nowhere near over. It's only barely starting. . .

Here's the PNAS commentary on the article, which adds some clarity. But no one's got enough clarity on hand for this subject yet.

Here's a fascinating short interview with Mark Smith of Case Western, a leading anti-amyloid-hypothesis guy in the Alzheimer's field. As you'd imagine, he's taking the recent failure of Lilly's gamma-secretase inhibitor in stride.

As you might imagine, he's not shy:

"Everything comes down to how one interprets data. There is a lot of scientific noise out there and most people like to play “follow the leader”. The structure of granting agencies actually discourages anything else. I sense the tide turning but think that the dead horse will be likely flogged for a while yet. For example, the Alzheimer’s field is already moving toward earlier and earlier “diagnosis”. Until these people are subjected to anti-amyloid approaches the field will continue [to support the amyloid theory].

I have received a lot of stick for my scientific talks where for over a decade I have challenged the amyloid hypothesis. I typically tell the audience that my views are controversial and that I would really appreciate someone pointing out a flaw in my logic or presenting evidence that shows that I am wrong. Neither has ever happened."

My time's been in short supply the last few days, so I haven't had a chance to blog about the latest response from Sirtris regarding their compounds and assays. It's coming! I'm doing a side-by-side with the earlier papers calling their results into question.

A reminder, for those in town for the ACS meeting. If you're interested, there will be a "Lunch and Learn" panel discussion on chem/pharma blogging in the Ballroom West tomorrow, from 12 to 2 (PDF flyer). As the longest-standing chemistry blogger (perhaps the longest standing science blogger, for all I know), I'm glad to have a chance to speak.

I was just telling a reader by e-mail that when I started this site in 2002, that I wasn't sure how much I'd find to write about. But (for better or worse) the material just keeps on coming. . .

Ray Kurzweil has responded to the criticism of his Singularity Summit comments on reverse-engineering the brain, a chorus to which I added my voice here. He says that he was misquoted on the timeline and on the importance of genomic data for doing it.

His plan, he says, is to understand what level of complexity will be needed in order for a system to organize and adapt the way the brain does to stimuli, and the modular nature of its organization gives him hope that this can be realized:

For example, the cerebellum (which has been modeled, simulated and tested) — the region responsible for part of our skill formation, like catching a fly ball — contains a module of four types of neurons. That module is repeated about ten billion times. The cortex, a region that only mammals have and that is responsible for our ability to think symbolically and in hierarchies of ideas, also has massive redundancy. It has a basic pattern-recognition module that is considerably more complex than the repeated module in the cerebellum, but that cortex module is repeated about a billion times. There is also information in the interconnections, but there is massive redundancy in the connection pattern as well.

Fine. But even that argument triggers the reaction in me that Kurzweil's statements often do. I wasn't aware that we had "modeled, simulated, and tested" a cerebellum yet, for one thing. If that's so well worked out, where is it? Why aren't industrial robots a lot more coordinated? I assume that one reason is that we haven't done it with four billion processing modules yet. But if not, does that really qualify as something that's been tested? Will it all really just be a matter of scaling up, or will more subtle features become important along the way?

He also goes on to say that "We have sufficiently high-resolution in-vivo brain scanners now that we can see how our brain creates our thoughts and see our thoughts create our brain." I'd disagree with that statement. The resolution of brain imaging techniques has been improving steadily, but it's still crude compared to what we're going to need. Every time we improve it, we find that things are more complicated than we thought.

If any of Kurzweil's exponential-growth predictions are to come true, though, it'll be the ones that involve computing power most directly, since that's where this sort of growth has come most reliably and spectacularly. I just don't think that our understanding increases at the same rate - and not every problem will find a solution through our ability to throw more processing power at it.

How do I reconcile this attitude of mine with my reasons-for-optimism post of the other day? Well, as I've said, we don't need miracles in drug discovery (although I'll welcome any that might show up). We just need to do things a little bit better than we do already - it's that young a field, and we're that poor at it. Compared to what we could know, and what we might be able to do, we're still way back on the curve. When your clinical failure rate is 90%, anything you can do better is an improvement. I'm not asking to (or claiming that we will) figure out predictive human toxicology in ten years. I just want to fail miserably eight out of ten times, instead of nine. And thus double the number of drugs coming to market. . .

A reader at one of the big pharma companies sends along this note:

. . .Over my 10 years or so of experience, I have seen a severe decline in risk tolerance at my company, and other large companies as well. When we put a project forward, we are told that either: (a) There are too many unknowns, the target is not well established, and therefore the risk in putting forward the large sums of money required for development are too high; or (b) There are too many other players in the market already and we would never be able to capture enough market share to justify the investment required to go forward. The band considered acceptable in the risk/benefit spectrum has become so narrow that it is like threading a needle with your feet.

I believe that this risk aversion is due to the escalating cost of developing new drugs. Big Pharma has invested such a tremendous amount of money into the infrastructure they deemed necessary to increase project turnaround time that any drug that hoes forward has to be seen as a guaranteed blockbuster or it is considered a failure.

Film buff that I am, I use a Big Studio Production vs. Independent Film analogy when I discuss this with people outside the profession. For example, the film Avatar cost about 300 million to make. That means that if it brings in a mere 50 million in ticket sales, it is a catastrophic failure for the studio. Paranormal Activity on the other hand cost a few tens of thousands of dollars to make. Bringing in 50 million dollars in ticket sales would exceed the filmmakers wildest dreams of avarice.

The end result is that the Big Studio has to KNOW that Avatar will bring in greater than 300 million dollars in ticket sales or it cannot take the risk. Therefore only tried and true box office magic directors like James Cameron are given the opportunity to work at that level. On the other end of the spectrum, an independent film distribution company is willing to take on a high risk project like Paranormal Activity because even a failure will not destroy the comany, and the rewards of success (even if moderate by Big Studio standards) is very high.

So, has Big Pharma doomed itself by massively inflating its drug discovery infrastructure in a misguided attempt to stregnthed its pipeline (which was clearly a failure)? Or is it the regulatory agencies that require such vast and expensive trials that are the cause of this risk aversion? Is there a solution?

Well, the Hollywood analogy has been made before, but that's because it's a pretty good one. There are a few places where it breaks down, though. Some of these are unfavorable to the drug business:

1. Copyright. It lasts a lot longer than patent rights. I think that copyright has been extended to ridiculous levels in the US, but it's always been significantly longer than patent terms. So a studio has a much longer time to makes its money back.

2. Regulatory affairs. There's no FDA approval process for a new film. You think it up, you get it shot and produced, you release it, and good luck to you. The drug industry hasn't worked that way since the 1930s.

3. Cycle time. It takes a lot longer to get a drug project through than it takes to get a movie done. And since time is most definitely money, this hurts.

4. Toxicity and liability. While it's true that a bad film might make you feel sick, it's not going to lead to anything actionable in court. Bad news on a new drug's side effects or performance most definitely will, though. And how.

5. Costs and benefits. A movie, from the consumer's standpoint, is a momentary purchase, made with a small amount of discretionary income. If it delivers, great - if not, no harm done, other than some wasted time and a bit of cash. Drugs, of course, are a much more high-stakes business, both in their pricing and in their utility. And they affect a person's health, which is about as fundamental a thing as you can mess with, and moves any transaction up into a whole new spotlight.

On the other hand, there are some problems that the studios face that we don't:

1. Limits of copyright. While copyright goes on next to forever, it's still easy to move a new film or book right up next to an existing work. Movies get ripped off much more quickly than drugs can be, and often more blatantly. That shorter cycle time cuts both ways.

2. Easier copying. You can find pirated versions of first-run movies pretty quickly - they're not always great, but there's a market. Lots of free stuff gets tossed around in digital formats, too. Drugs are much harder to truly copy, and an inferior version is much, much less attractive.

3. Fashion. An antihypertensive drug from thirty years ago doesn't wear funny-looking retro clothes or pick up a mobile phone the size of a loaf of bread. It lowers your blood pressure, same as always. There may be better ones around now, but it'll still work exactly as it did when it came on the market.

All that said, I think that the key point here is that there's no equivalent in the drug industry to indie filmmaking, which is too bad. Our fixed costs are much, much, higher due to the field we operate in - human health and the regulations around it. My question is - is there any way to bring these down? Of course, that's what everyone in the business has been asking for some time now.

Because if we can't, we're going to see even more of the behavior that my correspondent noted. Risk aversion, I might add, can be fatal to research-driven companies. Our whole business is founded on taking risks, and if the costs are pushing us to deny that, we have a huge conflict right at the center of the whole enterprise. . .

And yeah, I realize that this doesn't help too much with the "less depressing" promise I made for this week!

I have another journalistic blog request for those who are willing to help out. The folks at C&E News were following that recent alternative-careers-for-chemists post with interest, and are working on a story along the same lines.

Susan Ainsworth, a senior editor in Dallas, is looking to talk to chemists who've had to retool for new careers. She's interested in looking at movement in both directions, too - what happens if and when people try to come back into the field? Anyone who would like to help out can contact her at S_Ainsworth-at-acs.org. Thanks!

All right, given the way things have been going the last few years, it's easy to wonder if there's a place for medicinal chemistry at all - even if there's a place for drug discovery. There is. People are continuing to get sick, with diseases that no one can do much about, and the world would be a much better place if that weren't so. I also believe that such treatments are worth money, and that the people who devote their careers to finding them can earn a good living by doing so.

So why are fewer of us doing so? Because - and it needs no ghost come from the grave to tell us this - we're not finding as many of them as we need to, and it's costing us too much when we do. That's not sustainable, but drug discovery itself has to continue. We can't go on, we'll go on. But what we have to do is find new ways of going on.

I refuse to believe that those ways aren't out there somewhere. We do what we do so poorly, because we still understand so little - I can't accept that this is the best we're capable of. It won't take miracles, either. Think of the clinical failure rates, hovering around 90% in most therapeutic areas. If we only landed flat on our faces eight out of ten times in the clinic, we'd double the number of compounds that get through.

I think that we're in the worst stage of knowledge about disease and the human body. We have enough tools to get partway into the details, but not enough to see our way through to real understanding. Earlier ages were ignorant, and (for the most part) they knew it. (Lewis Thomas's The Youngest Science
has a good section on medicine as his own father practiced it - he was completely honest about how little he could do for most of his patients and how much he depended on placebos, time, and hope). Now, thanks to advances in molecular and cell biology, we've begun to open a lot of locked boxes, only to find inside them. . .more locked boxes. (Sorry about all these links. For some reason literature is running away with me this morning). We get excited (justifiably!) at learning things that we never knew, uncovering systems that we never suspected, but we've been guilty (everyone) of sometimes thinking that the real, final answers must be in view. They aren't, not yet.

Pick any therapeutic area you want, and you can see this going on. Cancer: it starts out as dozens of dread diseases, unrelated. Then someone realizes that in each case, it's unregulated cell growth that's going on. The key! Well, no - because we have no idea of how unregulated cell growth occurs, nor how to shut it off. Closer inspection, years and years of closer inspection, yields an astonishing array of details. Growth factor signaling, bypassed cell-death switches and checkpoints, changes in mitotic pathways, on and on. Along the way, many of these look like The Answer, or at least one of The Answers. Think about how angiogenesis came on as a therapeutic idea - Judah Folkman really helped get across the idea that some tumors cause blood vessels to grow to them, which really was a startling thought at the time. The key! Well. . .it hasn't worked out that way, or not yet. Not all tumors do this, and not all of them totally depend on it even when they do, and the ones that do turn out to have a whole list of ways that they can do it, and then they can mutate, and then. . .

There, that's where we are right now. Right in the middle of the forest. We know enough to know that we're surrounded by trees, we know the names of many of them, we've learned a lot - but we haven't learned enough yet to come out the other side. But here's the part that gives me hope: we keep on being surprised. Huge, important things keep on being found, which to me means that there are more of them out there that we haven't found yet. RNA! There's one that's happened well in the middle of my own professional career. When I started in this business, no one had any clue about RNA interference, double-stranded RNAs, microRNAs, none of it. All of it was going on without anyone being aware, intricate and important stuff, and we never knew. How many more things like that are waiting to be uncovered?

Plenty, is my guess. We keep pulling back veils, but the number of veils is finite. We're still ignorant, but we're not going to remain ignorant. We will eventually know the truth, and it'll do what the truth has long been promised to do: make us free.

But we don't have to wait until we know everything. As I said above, just knowing a bit more than we do now has to help. A little more ability to understand toxicology, a better plan to attack protein-protein targets, more confidence in what nuclear receptors can do, another insight into bacterial virulence, viral entry, cell-cycle signaling, glucose transport, lipid handling, serotonin second messengers, bone remodeling, protein phosphorylation, immune response, GPCR mechanisms, transcription factors, cellular senescence, ion channels. . .I could go on. So could you. The list is long, really long, and any good news anywhere on it gives us something else to work on, and something new to try.

So this is a rough time in the drug industry. It really is. But these aren't death throes. They're growing pains. We just have to survive them, either way.

News like today's gamma-secretase failure makes me want to come down even harder on stuff like this. Ray Kurzweil, whom I've written about before, seems to be making ever-more-optimistic predictions with ever-more-shortened timelines. This time, he's saying that reverse-engineering the human brain may be about a decade away.

I hope he's been misquoted, or that I'm not understanding him correctly. But some of his other statements from this same talk make me wonder:

Here's how that math works, Kurzweil explains: The design of the brain is in the genome. The human genome has three billion base pairs or six billion bits, which is about 800 million bytes before compression, he says. Eliminating redundancies and applying loss-less compression, that information can be compressed into about 50 million bytes, according to Kurzweil.

About half of that is the brain, which comes down to 25 million bytes, or a million lines of code.

This is hand-waving, and at a speed compatible with powered flight. It would be much less of a leap to say that the Oxford English Dictionary and a grammar textbook are sufficient to write the plays that Shakespeare didn't get around to. And while I don't believe that the brain is a designed artifact like The Tempest (or Tempest II: The Revenge of Caliban), I do most certainly believe that it is an object whose details will keep us busy for more than ten years.

Saying that its entire design is in the genome is deeply silly, mistaken, and misleading. The information in the genome takes advantage of so much downstream processing and complexity in a way that no computer program ever has, and that makes comparing it to lines of code laughable. I mean, lines of code have basically one level of reality to them: they're instructions to deal with data. But the genomic code is a set of instructions to make another set of instructions (RNA), which tells how to make another even more complex pile of multifunctional tools (proteins), which go on to do a bewildering variety of other things. And each of these can feed back on themselves, co-operate with and modulate the others in real time, and so on. Billions of years of relentless pressure (work well, or die) have shaped every intricate detail. The result makes the most complex human designs look like toys.

So here I am, absolutely stunned and delighted when I can make tiny bits of this machinery alter their course in a way that doesn't make the rest of it fall to pieces - a feat that takes years of unrelenting labor and hundreds of millions of dollars. And Ray Kurzweil is telling me that it's all just code. And not that much code, either. Have it broken down soon we will, no sweat. Sure.

I see that PZ Myers has come to the same conclusion. I don't see how anyone who's ever worked in molecular biology, physiology, cell biology, or medicinal chemistry could fail to, honestly. . .

Well, well, well. We finally have solid clinical data from a large trial of a gamma-secretase inhibitor for Alzheimer's disease. And it doesn't work.

Background, for those outside the field: a hallmark of Alzheimer's is the appearance of plaques in the brain. These are insoluble clumps of a protein called amyloid-beta, surrounded by dead and dying neurons. This amyloid is split off (for some reason) from the middle of a larger precursor protein (APP), and there are two enzymes that make the cuts to release it: gamma-secretase and beta-secretase. Shutting down one or both of those has long been seen as the most direct route to keeping amyloid from accumulating, and compounds that do this have been sought for at least twenty years now.

Now this is interesting. The road to secretase inhibition data in the clinic has been a long one, to say the very least - I worked in this field myself in the early 1990s, when we were still guessing at the enzymes involved. I would not like to even guess about the man-hours that have been spent along the way. Gamma-secretase has been a beast of a target. One nasty surprise along the way was the discovery that it also processes Notch, which is a developmental signaling pathway that you'd really rather avoid, but people have persevered, and pushed compounds into the clinic.

(As an aside, I'd have to say that beta-secretase has been even harder. There are an awful lot of structures out there billed as beta-secretase (BACE) inhibitors - and so they are, in your choice of labware. Despite huge efforts, it's been extremely hard to make an inhibitor with a reasonable chance of getting into the brain and being a drug. The only one I know of is CTS21166, from CoMentis, about which news has been rather scarce recently).

Myriad had taken a sort-of kind-of gamma-secretase inhibitor (Flurizan) into the clinic, and failed dismally. But Eli Lilly's semagacestat (LY450139) has long been the most advanced pure gamma-secretase inhibitor. It inhibits the enzyme directly, and had shown dose-dependent lowering of amyloid formation in humans, which is all you can ask. There were side effects noted from Notch, mostly in the GI tract, but the profile was still good enough to go on into Phase III two years ago. And now we have the results.

Nothing. Worse than nothing - they saw real declines in cognitive function compared to the placebo group. It's not getting as much play in the news this morning, but it also appears - insult to injury - that the drug was associated with a greater risk of skin cancer. Update: a commenter points out that this risk was known). Lilly has halted any development, and told all the study centers to stop dosing immediately. All the patients who received it will be monitored to see how they do over the next few months.

This is about as bad a result as could possibly be obtained, and I think it really has to torpedo the idea of gamma secretase as a drug target. Unless someone comes up with a very compelling and intricate argument to explain these results, I don't see how anyone can risk going down this particular road again. What must they be thinking today over at Bristol-Myers Squibb, where they've been developing a direct competitor, BMS708163? And how about the other drug candidates behind them?

And what does this say about the amyloid hypothesis itself? Nothing good. This is the crucial period for the whole idea, with several different approaches finally yielding late-stage clinical data. And it's starting to look as if the whole idea may have been just a terrible diversion.

As if one were needed, here's an example of how rough the state of current oncology therapy is today. Avastin, the antibody-based therapy from Genentech/Roche, had been approved (conditionally) for advanced breast cancer, based on a study showing about a five-month benefit in tumor growth. (Everyone should already know that such numbers, for many types of cancer, are indeed enough to get an indication approved, and everyone has, I'm sure, already decided what they think about that.)

But the approval came with a requirement to follow up on those results. For one thing, the study that led to conditional approval didn't show much of a survival benefit, making the approval itself controversial at the time.. The follow-up work has shown that those initial results were right on target. For metastatic breast cancer, Avastin has something like a month-and-a-half survival benefit. That probably doesn't outweigh the risks, and the FDA is seriously thinking about revoking that earlier approval.

Based on these numbers, I think that they should go ahead and do that. The whole point of conditional or accelerated approval is that it can go either way when the harder numbers come in, and in this case, it seems pretty clear that the benefit isn't there. No one cares about tumor growth if it doesn't affect survival or (at the very least) quality of life. And in this case, the later studies have suggested that even the earlier tumor growth numbers were too optimistic. You have to be willing to abide by the evidence.

Because of Avastin's high cost, this is probably going to turn into a rationing-health-care argument - in fact, it probably has already. But I'm not even talking cost here. Avastin, by the evidence we have, does not seem to help advanced breast cancer patients. It wouldn't help them even if it were free.

Word is now that Genzyme's manufacturing problems won't be solved for years, which has people wondering if Sanofi-Aventis (or anyone) will feel safe making a bid for them. That's the single biggest issue hanging over the company, and that's an awful lot of uncertainly to be taking on.

If so, it looks more and more like whoever set up this trade will end up doing just fine on it. . .

The topic of new drugs for cancer has come up repeatedly around here - and naturally enough, considering how big a focus it is for the industry. Most forms of cancer are the very definition of "unmet medical need", and the field has plenty of possible drug targets to address.

But we've been addressing many of them in recent years, with incremental (but only rarely dramatic) progress. It's quite possible that this is what we're going to see - small improvements that gradually add up, with no big leaps. If the alternative is no improvement at all, I'll gladly take that. But some other therapeutic areas have perhaps made us expect more. Infectious disease, for example: the early antibiotics looked like magic, as patients that everyone fully expected to die started asking when dinner was and when they could go home. That's what everyone wants to see, in every disease, and having seen it (even fleetingly), we all want to have it happen again.

And it has happened for a few tumor types, most notably childhood leukemia. But we definitely need to add more to the list, and it's been a frustrating business. Believe me, it's not like we in the business aiming for incremental improvements, a few weeks or months here and there. Every time we go after a new target in oncology, we hope that this one is going to be - for some sort of cancer - the thing that completely knocks it down.

We may be thinking about this the wrong way, though. For many years now, there have been people looking at genetic instability in tumor cells. (See this post from 2002 - yes, this blog has been around that long!) If this is a major component of the cancerous phenotype, it means that we could well have trouble with a target-by-target approach. (See this post by Robert Langreth at Forbes for a more recent take). And here's a PubMed search - as you can see, there's a lot of literature in this field, and a fair amount of controversy, too.

That would, in fact, mean that cancer shares something with infectious disease, and not, unfortunately, the era of the 1940s when the bacteria hadn't figured out what we could do to them yet. No, what it might mean is that many tumors might be made of such heterogeneous, constantly mutating cells that no one targeted approach will have a good chance of knocking them down sufficiently. Since that's exactly what we see, this is a hypothesis worth taking seriously.

There are other implications for drug discovery. Anyone who's worked in oncology knows that the animal tumor models we tend to use - xenografts of human cell lines - are not particularly predictive of success. "Necessary but nowhere near sufficient" is about as far as I'd be willing to go. Could that be because these cells, however vigorously they grow, have lost (or never had) that rogue instability that makes the wild-type tumors so hard to fight? I haven't seen a study of genetic instability in these tumor lines, but it would be worth checking.

What we might need, then, are better animal models to start with - here's a review on some efforts to find them. From a drug discovery perspective, we might want to spend more time on oncology targets that work outside the cancer cells themselves. And clinically, we might want to spend more time studying combinations of agents right from the start, and less on single-drug-versus-standard-of-care studies. The disadvantage there is that it can be hard to know where to start - but we need to weigh that against the chances of a single agent actually working

. . .next week. Less depressing. I promise!

I'm of two minds on this New York Times article on Alzheimer's research. It details some recent progress on biomarkers for the disease, and that work does look to be useful. A lot of people have proposed diagnostics and markers for Alzheimer's and its progression over the years, but none of them have really panned out. If these do, that's something we haven't had before.

But my first problem is something we were talking about here the other day. Biomarkers are not necessarily going to help you in drug development, not unless they're very well validated indeed. We really do need them in Alzheimer's research, because the disease progression is so slow. And this effort is really the only way to find such things - a good-sized patient sample, followed over many years. But unfortunately, 800 people (divided out into different patient populations) may or may not be enough, statistically. We're now going to have to take the potential assays and markers that this work has brought up and see how well they work on larger populations - that's the only way that they'll be solid enough to commit a clinical trial to them. Both the companies developing drugs and the regulatory agencies will have to see convincing numbers.

That general biomarker problem is something we really can't do anything about; the only cures are time, effort, money, and statistical power. So it's not a problem peculiar to Alzheimer's (although that's a tough proving ground), or to this collaborative effort. But now we come to the collaborative effort part. . .overall, I think that these sorts of things are good. (This gets back to the discussions about open-source drug discovery we've been having here). Bigger problems need sheer manpower, and smaller ones can always benefit from other sets of eyes on them.

The way that this Alzheimer's work puts all the data out into the open actually helps with that latter effect. All sorts of people can dig through the data set, try out their hypotheses, and see what they get. But I think it's important to realize that this is where the benefit comes from. What I don't want is for people to come away thinking that the answer is that we need One Big Centralized Effort to solve these things.

My problem with the OBCE model, if I can give it an acronym, is that it tends to cut back on the number of ideas and hypotheses advanced. Big teams under one management structure don't tend to work out well when they're split up all over the place. There's managerial (and psychological) pressure, from all directions, to get everyone on the same idea, to really get in and push that one forward with all the resources. This is why I worry about all the consolidation in the drug industry: fewer different approaches get an airing when it's all under the roof of one big company.

So this Alzheimer's work is just the sort of collaboration I can admire: working on a big problem, sharing the data, and leaving things open so that everyone with an idea can have a crack at it. I just hope that people don't get the wrong idea.

Update - see below for more on this story. GSK has reacted quickly. . .

Now this seems rather odd. According to Xconomy, two former Sirtris higher-ups have formed a nonprofit foundation which is selling resveratrol online.

Michelle Dipp, a Sirtris-turned-Glaxo executive, confirmed that the nonprofit that she and former Sirtris CEO Christoph Westphal co-founded last year has started online sales of resveratrol. Dipp leads the effort on the off hours when she isn’t doing her main job as senior vice president of Glaxo’s Center of Excellence for External Drug Discovery.

While the group is charging $540 for a one-year supply of resveratrol, Dipp says that the nonprofit is selling the supplements for cost and is not profiting from the sales.

And thanks to Hatch-Waxman, since this is being offered as a "dietary supplement", hey, it can go straight into people - people with $540, anyway:

To be clear, this resveratrol operation is a volunteer effort that Dipp and Westphal do on the side. Both are still employees of Glaxo, and they have also started a Boston venture firm called Longwood Founders Fund with fellow Sirtris co-founder Rich Aldrich.

“Our main business is brining new drugs to patients through our work at Longwood and (Glaxo),” says Dipp, who is president of the Healthy Lifespan Institute. “But there was so much demand for (resveratrol).”

I really don't know what to make of this. This formulation of resveratrol would appear to be basically SRT501, which has been involved in a number of clinical trials (and unexpectedly dropped out of one not too long ago). I can't recall another case where an investigational drug has also been sold as a dietary supplement, by some of the same people, who are working both for the company funding the trials and for a nonprofit foundation. I mean, what if GSK/Sirtris find a clinically relevant use for resveratrol? Why buy it from them if you can get it at cost? Or would all that change if SRT501 gets FDA approval? Makes a person's head hurt, it does. . .

Update - GSK has now asked Dipp and Westphal to resign from their institute, saying that they didn't realize that they were selling resveratrol. That didn't take long!

Readers may remember Generex, the company that's developing a buccal insulin spray. I'm not sold on their technology or their prospects, to put it mildly. In this post I took a look at the investment outfit that did a stock transaction with the company, and found them not to my taste, either.

Well. . .now to MannKind. They've been developing an inhaled insulin formulation (not a buccal spray, I hasten to add) for a long time now. Everyone who's ever worked in the area has had to be in it for the long haul, as the Pfizer/Exubera story will show. It has been long, and it has been expensive, and there have been worries that MannKind might not have enough money to stay the course. They've been seeking a partner for some time now.

Back in March the company got a response from the FDA about the prospects for the drug, which had been delayed. The agency has recently accepted the company's NDA resubmission, with a decision due by the end of the year.

But now comes news that the company is doing a stock-swap deal involving Seaside 88. Given how Seaside 88 looks on close inspection (see that link in the first paragraph), I find it hard to imagine that they'd be anyone's first choice for financing. I have no stock or option position in MannKind - long or short. But if I were long the company, this news would not be making me happy.