In the Pipeline

Iran: Politics and Technology Update

Fri, 10 Jul 2009 10:05:59 -0500

I wanted to make another brief excursion here, since (as many of you will have seen on the news), the situation in Iran is still very volatile indeed. The proxy-server efforts that I've spoken about here have been overtaken by events - plaintext proxies are basically out of the picture, thanks to countermeasures by the Iranian government.

But there are other ways to get information in and out, as the number of video clips from yesterday's protests make clear. For a roundup, see this post from Massachusetts's own Tehran Bureau: "Geeks Around the Globe Rally to Help Iranians Online". I'm glad to number myself among them.

One aspect of said geekdom is supporting Tor. I'm running a relay on my home computer - that's my machine, the relay named "levoglucosan" on this list of current routers. Setting up Tor took about five minutes to (but no real geek skills whatsoever, as opposed to getting the proxy servers going). Tor's getting a lot of use, as the Tehran Bureau post makes clear:

“Before the election we were seeing about one to two hundred new users [from Iran] per day,” says Andrew Lewman, executive director of The Tor Project.
“Right after the election and as the protests started we started seeing that spike up into 700 – 1,000 per day. Now we’re up to about 2,000 new users a day and around 8,000 connections sustained at any time, which is a huge, dramatic increase.”

The Canadians are doing their part via Psiphon, which has also had thousands of Iranian users recently. Another new effort is Haystack, a new anonymous-access tool which has been specifically designed to circumvent the Iranian regime's web filtering tools. It's modeled on Freegate, which has been giving the Great Firewall of China fits (and has also been useful in Iran, although they've had to cut access back to keep their Chinese bandwidth up). Haystack appears to have had its first test inside Iran yesterday, and appears to be working just as planned. With any luck, it'll soon be giving fits to the Iranian web censors, too: the kind of government that beats unarmed protestors in the streets, that breaks down doors in the middle of the night to haul people away just for suggesting in public that they don't like their leaders.

As a scientist, I believe in freedom of expression and freedom of inquiry. I've donated money and time to the efforts linked to above, and I'd like to urge that others do the same if they can.

mTOR, Rapamycin, and Lifespan: A Startling Study

Fri, 10 Jul 2009 06:35:16 -0500

A new paper coming out in Nature is getting a lot of attention, and well it should. This is some of the more dramatic anti-aging news that's been reported to date. (The accompanying editorial is also surely the first time anyone's quoted "Stairway to Heaven" in Nature).

The work hinges on a kinase enzyme called TOR (you often see an "m" in front of it, for "mammalian"). TOR, in accordance with the best gotta-name-it-something traditions of biochemistry, stands for "target of rapamycin", by which you would deduce (correctly) that rapamycin was discovered well before TOR. Rapamycin's a complex natural product first isolated from bacteria in a soil sample from Easter Island (Rapa Nui) - right here, in fact. In the late 1980s and early 1990s it was (along with another macrolide immunosuppresant, FK-506) the subject of a huge amount of research. (Note that FK-506 and rapamycin, though similar, still have some major differences in mechanism - unraveling these was most definitely nontrivial). Both compounds have strong immunosuppressive properties - the hope was that one or the other might prove to be some sort of universal transplant drug, among other things.

Rapamycin isn't that, but it's still useful, particularly in kidney transplants. And since TOR is involved in a lot of important cellular processes (brace yourself), inhibition of it by rapamycin and synthetic molecules has been studied extensively for other actions. The most interesting (well, perhaps until now) has been as an anticancer therapy. That alone illustrates the trickiness of this area, since one problem with any immunosuppressive therapy is a significantly higher risk of cancer. Decoupling these two effects has occupied a lot of time and effort over the years; that last link should give you an idea of the magnitude of the task.

But rapamycin has also shown life-extending properties in simple organisms, and this latest paper extends this effect to mice. The NIH group studying this had their problems, though - just adding the compound to rodent chow wasn't enough to achieve useful blood levels. More formulation work had to be done to produce an encapsulated version that could make it past the upper gut, and by the time that was worked out, the large cohort of mice set aside for the experiment was. . .well, rather more aged than planned.

But they went ahead with the experiment anyway, starting them off at 600 days old, which is roughly a 60-year-old human. Startlingly, the compound still extends life span, by about 14% in the female mice and 9% in the males. At ages where about 5% of the control mice were still alive, some 20% of the treated mice were still going. That's a very significant result, especially considering the late start. All in all, this looks like the most dramatic mid-to-later lifespan intervention that anyone's ever seen in a mammal. (Caloric restriction, for example, has been basically useless if started at the 600 day mark in mice, and no weight losses were seen here). There's a rapamycin study under way with mice in the prime of rodent life (starting at 270 days), and the preliminary results look quite similar (with again a stronger effect in the females).

The causes of death don't seem to have altered. A good sample of animals from both groups were checked by necropsy, and nothing significant was noted. That seems rather surprising, because the blood levels of the compound are (at least from what I can see) rather high. The paper mentions that the mice had 60 to 70 ng/mL rapamycin, and looking around, I find blood levels of 15 ng/mL mentioned as effective in tumor suppression in one mouse model, and the immunosuppressive doses seem to be similar. I'd be glad to hear from anyone who knows more about rapamycin dosing in mice, though; it's definitely outside my range of experience.

Are people going to run out and start taking the stuff? It wouldn't surprise me, although I'd have to say that that's a bad idea at the moment. There's an awful lot that we don't understand about the tradeoffs between aging, cancer, and the immune response, and I'd hate to end up on the wrong side of that bet. Jumping straight to humans is too big a leap for now, but remember - there are a lot of other mTOR inhibitors out there in development (try this paper for starters). If we can narrow down which pathways are important for lifespan (and believe me, there are people thinking hard about this right now, especially after this paper), then there could be some very interesting opportunities

Too Many Scientists?

Thu, 09 Jul 2009 07:13:53 -0500

Let's open up again that contentious subject of scientific jobs. In my entire memory, I have never once heard anyone editorialize that we are turning out too many scientists and engineers. A looming shortage has always been, well, looming. And these days, it's easy to wonder how much of a shortage there can possibly be. This USA Today article (link thanks to a longtime reader of this site) rounds up a lot of quotes from people in the game, and wonders about the same thing:

While there have been warnings for more than 50 years, a renewed push over the past four years has earned the attention of both the Bush and Obama administrations.
Speaking to the National Academy of Sciences in April, Obama announced "a renewed commitment to education in mathematics and science," fulfilling a campaign promise to train 100,000 scientists and engineers during his presidency.

Only problem: We may not have jobs for them all.

As the push to train more young people in STEM — science, technology, engineering and math — careers gains steam, a few prominent skeptics are warning that it may be misguided — and that rhetoric about the USA losing its world pre-eminence in science, math and technology may be a stretch.

I think that one muddying factor (as the article mentions later on) is that lumping all scientists, mathematicians, and engineers together isn't very useful. Civil engineering is very different from optimizing computational algorithms, which is quite different from medicinal chemistry, which is quite different from semiconductor research. When I hear people talk as if all these were part of a coherent whole, I sometimes get the impression that, because of the speaker's own educational background, they must seem to be one somehow. But it doesn't make sense to me.

That said, I know that employment prospects in our own field of drug research are very much on everyone's mind. The last year or two have been the worst I've ever seen for hiring in the industry. I go back only to 1989, but longer-serving colleagues report the same feelings. Looking over the ads that appear in the likes of C&E News certainly doesn't make a person think differently.

The unimpressive rate of successful new drug introductions, coupled with the rising costs of R&D (especially clinical trials), was already squeezing us before this whole economic downturn hit. Outsourcing was one big response to that (again, pre-downturn), and we've hashed over that issue around here several times. (The downturn's effect on the outsourcing business has been mixed, by the way, as far as I can see. Some companies may have increased their offshore work, but others have cut back on it as one form of discretionary spending).

But back to the big questions, which are pretty damned hard to answer: are there technical/scientific fields where the US has too many people for the jobs available? If so, are these situations part of various cyclical trends, or are they full secular downturns, or what? Did we get there by training too many people for a job market that was otherwise in reasonable shape, or did the number of positions start to fall and not hold up that end of the process, or both? And where are all these variables going in the future?

I don't know, and I'm willing to bet that no one else does, either. When you're listening to someone talk about these issues, though, I think that there are several things to look out for that might indicate that the person you're hearing has not thought things through well enough. First off, there's that everything-in-one-category problem that I mentioned above. Anyone who seriously wants to address the issue in that fashion hasn't, I'd say, worked on the problem long enough. Secondly, I think it's fair to say that anyone who seems to uncritically accept the idea of a severe shortage of manpower across the whole technical/scientific area is not arguing from a position of strength. Unfortunately, that category has, in the past few years, included people like Bill Gates, various cabinet secretaries, heads of the National Science Foundation, and other such riff-raff. This isn't helping to clear the air.

Next, anyone who brings up the numbers of Chinese and Indian graduates in these areas, especially anyone who just quotes numbers of "engineers" without breaking things down more, needs to think harder. It's true that impressively huge numbers can be quoted, but (sad to say) they're not all they're cracked up to be, at least not yet:

Even Asia's much-touted numerical advantage is less than it seems. China supposedly graduates 600,000 engineering majors each year, India another 350,000. The United States trails with only 70,000 engineering graduates annually. Although these numbers suggest an Asian edge in generating brainpower, they are thoroughly misleading. Half of China's engineering graduates and two thirds of India's have associate degrees. Once quality is factored in, Asia's lead disappears altogether. A much-cited 2005 McKinsey Global Institute study reports that human resource managers in multinational companies consider only 10 percent of Chinese engineers and 25 percent of Indian engineers as even "employable," compared with 81 percent of American engineers.

So there's that to consider. And we haven't even talked about the various solutions proposed, even stipulated what the problems are. Pour money into education? Industrial policy? Retraining? Tax incentives? It's a mess. I guess my main message is to beware of anyone who tries to tell you that it's a reasonably understandable one.

How Much Does the Drug Industry Spend on Marketing?

Wed, 08 Jul 2009 07:13:06 -0500

Anyone who defends the pharmaceutical industry has to be ready to hear, over and over and over, about how much it spends on sales and marketing versus R&D. This is thought to be a telling point about where the priorities really are. I've addressed this one several times, and my best response is to point out that sales and marketing are actually supposed to bring in more money than you spend on them, and do so more reliably than R&D in the short term.

There's now a very useful paper in Nature Reviews Drug Discovery looking at just this issue. The authors (from three universities in the US and Israel) are looking into the general question of which is the better use of money: put it into R&D for the long term, or promote existing products for the short term? I should make clear at the outset that those two options do line up in that way. R&D expenditures take years to pay off, if ever, given the amount of time that drug development takes. And marketing of a current product had better start paying off in a shorter time frame, because every patented drug is a wasting asset, constantly being eaten into by competition and by its time to patent expiration.

So which makes more financial sense? The authors numbers from the Wharton databases on publicly traded drug companies, looking at those with more than $50 million in sales. Using the company stock prices as a measure of value (J. Finance LVI(6), 2431–2456 (2001), I'm giving you references here), they found, in general, that R&D investments have a net positive effect, while increased promotion has a negative effect. (See also Rev. Account Stud. 7, 355–382 (2002), another journal I don't reference much). Both effects are larger for smaller companies, as you might expect, but they held up across the industry. The effect also holds up if you factor out the compensation packages of the top five executives of each company (which is a nice control to run, I have to say). And yes, since you ask, there is a negative effect on stock price that correlates to higher executive compensation, and I'm willing to bet that this effect holds for more than just the drug industry.

Since we're talking about stock prices, which are generally forward-looking, the way to interpret these results is probably that investors expect R&D expenditures to pay off in the long term, but actually expect sales and marketing expenditures to reduce long-term value. If that's so, then why spend money on marketing? The reason the authors propose is just what I'd been talking about: short-term reliability. Drug discovery and development is inherently risky, and promotion of existing products is (at least comparatively) more of a sure thing. Companies engage in a mix of the two to try to even the cash flow out. (And as the authors note, if executive compensation is tied more to short-term performance, then there's an incentive to go with the short-term gains).

In general, though, you'd figure that companies should invest more in R&D. And here's the real kicker: that's exactly what's been happening. As this graph from the paper shows, over the last thirty years expenditures in the Sales, General, and Administrative area have risen only slightly as a per cent of sales. The Cost of Goods Sold category (materials, physical plant, manufacturing facilities, etc.) has gone proportionally down, with an interesting excursion in the mid-1990s. (Note also that this used to be the leading category). And R&D expenditures (again, as a per cent of sales) rose in the 1980s, were flat in the 1990s, and have risen since then. Overall, since 1975, the proportion of money spent on R&D has more than tripled, from 5% to 17%.

This, I hardly need point out, does not fit the narrative of some of the e-mails and comments I get. Some perceptions of the drug industry have us, Back In the Old Days, as spending our money on R&D, only to slimily slide into becoming pure marketing businesses as time has passed, with our recent years being especially disgusting and rapacious. According to these figures, this is at the very least not accurate, and comes close to being the opposite of the truth. Comments are welcome - most welcome, indeed.

What's So Special About Ribose?

Tue, 07 Jul 2009 10:42:27 -0500

While we're on the topic of hydrogen bonds and computations, there's a paper coming out in JACS that attempts to answer an old question. Why, exactly, does every living thing on earth use so much ribose? It's the absolute, unchanging carbohydrate backbone to all the RNA on Earth, and like the other things in this category (why L amino acids instead of D?), it's attracted a lot of speculation. If you subscribe to the RNA-first hypothesis of the origins of life, then the question becomes even more pressing.

A few years ago, it was found that ribose, all by itself, diffuses through membranes faster than the other pentose sugars. This results holds up for several kinds of lipid bilayers, suggesting that it's not some property of the membrane itself that's at work. So what about the ability of the sugar molecules to escape from water and into the lipid layers?

Well, they don't differ much in logP, that's for sure, as the original authors point out. This latest paper finds, though, by using molecular dynamic simulations that there is something odd about ribose. In nonpolar environments, its hydroxy groups form a chain of hydrogen-bond-like interactions, particularly notable when it's in the beta-pyranose form. These aren't a factor in aqueous solution, and the other pentoses don't seem to pick up as much stabilization under hydrophobic conditions, either.

So ribose is happier inside the lipid layer than the other sugars, and thus pays less of a price for leaving the aqueous environment, and (both in simulation and experimentally) diffuses across membranes ten times as quickly as its closely related carboyhydate kin. (Try saying that five times fast!) This, as both the original Salk paper and this latest one note, leads to an interesting speculation on why ribose was preferred in the origins of life: it got there firstest with the mostest. (That's a popular misquote of Nathan Bedford Forrest's doctrine of warfare, and if he's ever come up before in a discussion of ribose solvation, I'd like to hear about it).

Another Thing We Don't Know

Tue, 07 Jul 2009 06:22:29 -0500

Hydrogen bonds are important. There, that should be an sweepingly obvious enough statement to get things started. But they really are - hydrogen bonding accounts for the weird properties of water, for one thing, and it's those weird properties that are keeping us alive. And leaving out the water (a mighty big step), internal hydrogen bonding is still absolutely essential to the structure of large biological molecules - proteins, complex carbohydrates, DNA and RNA, and so on.

But we don't understand hydrogen bonds all that well, dang it all. It's not like we're totally ignorant of them, for sure, but there are a lot of important things that we don't have a good handle on. One of these may just have been illustrated by this paper in Nature Structural and Molecular Biology by a group from Scripps. They've been working on understanding the fact that all hydrogen bonds are not created equal. By carefully going through a lot of protein mutants, they have evidence for the idea that H-bonds that form in polar environments are weaker than ones that form in nonpolar ones.

That makes sense, on the face of it. One way to think of it is that a hydrogen bond in a locally hydrophobic area is the only game in town, and counts for more. But this work claims that such bonds can be worth as much as 1.2 kcal/mole more than the wimpier ones, which is rather a lot. Those kinds of energy differences could add up very quickly when you're trying to understand why a protein folds up the way it does, or why one small molecule binds more tightly than another one.

Do we take such things into account when we're trying to compute these energies? Generally speaking, no, we do not - well, not yet. If these folks are right, though, we'd better start.

Update: note that the paper itself doesn't suggest that this is a new idea - they reference work going back to 1963 (!) on the topic. What they're trying to do is put more real numbers into the mix. And that's what my last paragraph above is trying to state (and perhaps overstate): it's difficult to account for these thing computationally, since they vary so widely, and since we don't have that good a computational handle on hydrogen bonds in general. The more real world data that can be fed back into the models, the better.

Argumentum ad Crumenam

Mon, 06 Jul 2009 10:13:41 -0500

There's been a raging battle going on in the comments to this post wherein I disparaged homeopathic medicine. I've been staying out of it, but I had to excerpt this comment, make by a persistent advocate for the miracle water:

In the meantime, homeopathy is practiced openly by learned men in Europe. Why is that? Are they THAT ‘superstitious’? That ‘stupid’? Or that ‘corrupt’. Seriously. Is Great Britain RULED by a bunch of superstitious idiots? The Royal family retains homeopaths as part of their medical staff.

I'll be glad to field that one. Why yes, since you ask, if the royal family pays homeopaths, then "superstitious idiots" seems to be a perfectly appropriate phrase. And anyone who believes that any member of a hereditary monarchy (or of any other rich family) has to be more intelligent because of their position. . .well, there are phrases to describe a person like that, too. Hey, we can even be thrifty and reuse "superstitious idiot". This is an old enough logical fallacy to have a Latin name; see above.

If you'd like to see someone else berate the House of Windsor for just these same failings, you can see Richard Dawkins do a first-class job of it here.

Farewell to Hard Copies

Mon, 06 Jul 2009 08:06:39 -0500

Someone's leaked an American Chemical Society memo to Nature, in which the VP of the publishing division talks about how the printed journals are going to be phased out. The ACS isn't confirming anything, but they're not denying it, either: it looks like the days of paper copies of their journals are numbered.

I've been expecting that. I used to have a print subscription to the Journal of Organic Chemistry back in the early and mid-1990s, and I took them with me in a move in 1997. I interrupted my subscription around that time, and never got around to renewing it. By then, online access was starting to become a more convenient way to locate old articles, and as the ACS improved their archives the advantages became overwhelming. Then I got used to following the new issues online, either by going to the journal's site or by RSS feeds.

So my boxed collection of several years of JOC sat in my basement, in bales of cobalt-blue-covered bricks of paper. I'd planned on moving them into my office, but didn't got around to it at first. That delay allowed the situation to turn into "Hmmm. . .not sure that I see the need to have these taking up the shelf space", which turned into "You know, I need to recycle these things". And gradually, that's just what I did.

When I joined the Wonder Drug Factory in '97, new print journals were still put out on a table in the library as they came in, for people to sit down and read. A few years later, the table was gone, and whole idea was sounding downright Victorian in retrospect. The company where I work now doesn't even have much of a real, printed-on-paper chemistry library at all. It's been years I last picked up a hard copy of any chemistry journal - when I see the cover illustration of a journal on its web site, I keep thinking of "Elegy Written in a Country Churchyard": Full many a flower is born to blush unseen / And waste its sweetness on the desert air. OK, I'm perhaps a bit weird in that respect. But you get the idea.

Printed copies of journals have some advantages. I used to read JOC in the laundromat when I lived in New Jersey, which kept the casual chit-chat down to a stark minimum, I can tell you. I think that the browsing effect of looking through a hard copy is only partially emulated by scrolling through an RSS feed - the old way, you could see all the details inside a paper as you flipped through, and often learned something. So in a way, I'll miss the bound versions. But then I think of those boxes in my basement, and I realize that there's really no other way.

Day Off

Fri, 03 Jul 2009 06:55:36 -0500

I'll be taking today off, as an addition to the Fourth of July weekend. I hope that my American readers enjoy some warm, sunny weather (of the kind that's been in very short supply around here). No matter what the conditions, though, I'll be making a large slow-cooked pork shoulder with plenty of hickory wood. I'll see everyone on Monday!

Jargon Will Save Us All

Thu, 02 Jul 2009 06:21:01 -0500

Moore's Law: number of semiconductors on a chip doubling every 18 months or so, etc. Everyone's heard of it. But can we agree that anyone who uses it as a metaphor or perscription for drug research doesn't know what they're talking about?

I first came across the comparison back during the genomics frenzy. One company that had bought into the craze in a big way press-released (after a rather interval) that they'd advanced their first compound to the clinic based on this wonderful genomics information. I remember rolling my eyes and thinking "Oh, yeah", but on a hunch I went to the Yahoo! stock message boards (often a teeming heap of crazy, then as now). And there I found people just levitating with delight at this news. "This is Moore's Law as applied to drug discovery!" shouted one enthusiast. "Do you people realize what this means?" What it meant, apparently, was not only that this announcement had come rather quickly. It also meant that this genomics stuff was going to discover twice as many drugs as this real soon. And real soon after that, twice as many more, and so on until the guy posting the comment was as rich as Warren Buffet, because he was a visionary who'd been smart enough to load himself into the catapult and help cut the rope. (For those who don't know how that story ended, the answer is Not Well: the stock that occasioned all this hyperventilation ended up dropping by a factor of nearly a hundred over the next couple of years. The press-released clinical candidate was never, ever, heard of again).

I bring this up because a reader in the industry forwarded me this column from Bio-IT World, entitled, yes, "Only Moore's Law Can Save Big Pharma". I've read it three times now, and I still have only the vaguest idea of what it's talking about. Let's see if any of you can do better.

The author starts off by talking about the pressures that the drug industry is under, and I have no problem with him there. That is, until he gets to the scientific pressures, which he sketches out thusly:

Scientifically, the classic drug discovery paradigm has reached the end of its long road. Penicillin, stumbled on by accident, was a bona fide magic bullet. The industry has since been organized to conduct programs of discovery, not design. The most that can be said for modern pharmaceutical research, with its hundreds of thousands of candidate molecules being shoveled through high-throughput screening, is that it is an organized accident. This approach is perhaps best characterized by the Chief Scientific Officer of a prominent biotech company who recently said, "Drug discovery is all about passion and faith. It has nothing to do with analytics."
The problem with faith-based drug discovery is that the low hanging fruit has already been plucked, driving would be discoverers further afield. Searching for the next miracle drug in some witch doctor's jungle brew is not science. It's desperation.

The only way to escape this downward spiral is new science. Fortunately, the fuzzy outlines of a revolution are just emerging. For lack of a better word, call it Digital Chemistry.

And when the man says "fuzzy outline", well, you'd better take him at his word. What, I know you're all asking, is this Digital Chemistry stuff? Here, wade into this:

Tomorrow's drug companies will build rationally engineered multi-component molecular machines, not small molecule drugs isolated from tree bark or bread mold. These molecular machines will be assembled from discrete interchangeable modules designed using hierarchical simulation tools that resemble the tool chains used to build complex integrated circuits from simple nanoscale components. Guess-and-check wet chemistry can't scale. Hit or miss discovery lacks cross-product synergy. Digital Chemistry will change that.

Honestly, if I start talking like this, I hope that onlookers will forgo taking notes and catch on quickly enough to call the ambulance. I know that I'm quoting too much, but I have to tell you more about how all this is going to work:

But modeling protein-protein interaction is computationally intractable, you say? True. But the kinetic behavior of the component molecules that will one day constitute the expanding design library for Digital Chemistry will be synthetically constrained. This will allow engineers to deliver ever more complex functional behavior as the drugs and the tools used to design them co-evolve. How will drugs of the future function? Intracellular microtherapeutic action will be triggered if and only if precisely targeted DNA or RNA pathologies are detected within individual sick cells. Normal cells will be unaffected. Corrective action shutting down only malfunctioning cells will have the potential of delivering 99% cure rates. Some therapies will be broad based and others will be personalized, programmed using DNA from the patient's own tumor that has been extracted, sequenced, and used to configure "target codes" that can be custom loaded into the detection module of these molecular machines.

Look, I know where this is coming from. And I freely admit that I hope that, eventually, a really detailed molecular-level knowledge of disease pathology, coupled with a really robust nanotechnology, will allow us to treat disease in ways that we can't even approach now. Speed the day! But the day is not sped by acting as if this is the short-term solution for the ills of the drug industry, or by talking as if we already have any idea at all about how to go about these things. We don't.

And what does that paragraph up there mean? "The kinetic behavior. . .will be synthetically constrained"? Honestly, I should be qualified to make sense of that, but I can't. And how do we go from protein-protein interactions at the beginning of all that to DNA and RNA pathologies at the end, anyway? If all the genomics business has taught us anything, it's that these are two very, very different worlds - both important, but separated by a rather wide zone of very lightly-filled-in knowledge.

Let's take this step by step; there's no other way. In the future, according to this piece, we will detect pathologies by detecting cell-by-cell variations in DNA and/or RNA. How will we do that? At present, you have to rip open cells and kill them to sequence their nucleic acids, and the sensitivities are not good enough to do it one cell at a time. So we're going to find some way to do that in a specific non-lethal way, either from the outside of the cells (by a technology that we cannot even yet envision) or by getting inside them (by a technology that we cannot even envision) and reading off their sequences in situ (by a technology that we cannot even envision). Moreover, we're going to do that not only with the permanent DNA, but with the various transiently expressed RNA species, which are localized to all sort of different cell compartments, present in minute amounts and often for short periods of time, and handled in ways that we're only beginning to grasp and for purposes that are not at all yet clear. Right.

Then. . .then we're going to take "corrective action". By this I presume that we're either going to selectively kill those cells or alter them through gene therapy. I should note that gene therapy, though incredibly promising as ever, is something that so far we have been unable, in most cases, to get to work. Never mind. We're going to do this cell by cell, selectively picking out just the ones we want out of the trillions of possibilities in the living organism, using technologies that, I cannot emphasize enough, we do not yet have. We do not yet know how to find most individual cells types in a complex living tissue; huge arguments ensue about whether certain rare types (such as stem cells) are present at all. We cannot find and pick out, for example, every precancerous cell in a given volume of tissue, not even by slicing pieces out of it, taking it out into the lab, and using all the modern techniques of instrumental analysis and molecular biology.

What will we use to do any of this inside the living organism? What will such things be made of? How will you dose them, whatever they are? Will they be taken up though the gut? Doesn't seem likely, given the size and complexity we're talking about. So, intravenous then, fine - how will they distribute through the body? Everything spreads out a bit differently, you know. How do you keep them from sticking to all kinds of proteins and surfaces that you're not interested in? How long will they last in vivo? How will you keep them from being cleared out by the liver, or from setting off a potentially deadly immune response? All of these could vary from patient to patient, just to make things more interesting. How will we get any of these things into cells, when we only roughly understand the dozens of different transport mechanisms involved? And how will we keep the cells from pumping them right back out? They do that, you know. And when it's time to kill the cells, how do you make absolutely sure that you're only killing the ones you want? And when it's time to do the gene therapy, what's the energy source for all the chemistry involved, as we cut out some sequences and splice in the others? Are we absolutely sure that we're only doing that in just the right places in just the right cells, or will we (disastrously) be sticking in copies into the DNA of a quarter of a per cent of all the others?

And what does all this nucleic acid focus have to do with protein expression and processing? You can't fix a lot of things at the DNA level. Misfolding, misglycosylation, defects in transport and removal - a lot of this stuff is post-genomic. Are we going to be able to sequence proteins in vivo, cell by cell, as well? Detect tertiary structure problems? How? And fix them, how?

Alright, you get the idea. The thing is, and this may be surprising considering those last few paragraphs, that I don't consider all of this to be intrinsically impossible. Many people who beat up on nanotechnology would disagree, but I think that some of these things are, at least in broad hazy theory, possibly doable. But they will require technologies that we are nowhere close to owning. Babbling, as the Bio-IT World piece does, about "detection modules" and "target codes" and "corrective action" is absolutely no help at all. Every one of those phrases unpacks into a gigantic tangle of incredibly complex details and total unknowns. I'm not ready to rule some of this stuff out. But I'm not ready to rule it in just by waving my hands.

Vanda Comes Back From the Dead

Wed, 01 Jul 2009 06:29:13 -0500

I wrote last summer about Vanda Pharmaceuticals and their difficulty getting a new antipsychotic Fanapt (iloperidone) through the FDA. At the time, they'd received one of those wonderful requests for more information from the agency, of the kind that spread cheer whenever they appear. I couldn't see how the company could clear this up without (probably) having to spend a lot of money that it didn't have, and I was very pessimistic about their survival.

And I was wrong. Big-time. Vanda received approval for iloperidone, in what is a major surprise not just for me, but for the company's hardy shareholders and for the few analysts left covering them. After congratulating the company, I feel like asking them "So, how did you do that, anyway?" To the best of my knowledge, the company didn't go back into the clinic - and it's hard to see how they even could have. Less than a year just isn't feasible from a standing start in an antipsychotic trial just on logistic grounds, let alone the fact that Vanda doesn't seem to have had the funds to even try.

So was this all just a regrettable misunderstanding? And if so, on whose part? Did the FDA misinterpret something, only to be argued back by the company? Or did Vanda mess something up in the original regulatory package? We may never know.

The question now that the dog has caught the mail truck is what to do with it. No deal has been announced yet to market the compound, and Vanda still doesn't seem to have the funds to sell it by itself. (Moreover, they don't seem to be recruiting a sales force). Some observers think that the company may have had time selling itself off, and that the run in the stock was overdone just for that reason.

In the meantime, though, the company should enjoy its good fortune (as should anyone who was holding its stock when the news hit). And readers of this blog should make a note that, in case there was any doubt, I can be completely, totally wrong about the field I work in. . .

Voluntary, You Say?

Tue, 30 Jun 2009 10:19:30 -0500

Sanofi is saying "no layoffs" in their announcement today, but is instead counting on "voluntary staff departures". Here's the press release, courtesy of Fierce Biotech, notable for its relentless insistence on not capitalizing the name of the company.

I'm not sure how those voluntary departures are supposed to work - I can tell you it would take a lot to get anyone in R&D to volunteer to leave their job in this climate. So, generous - very generous - buyouts are one way, and sheer attrition is another (although turnover must not be so high these days either, with fewer places to go). The press release is rather short on details. Don't believe me? Chew on this:

"To implement this new R&D model, sanofi-aventis will group researchers in more productive structures and engage in recruiting and training to adapt the profiles and skills of its collaborators to the demands of these mutations. The model also includes strengthening 'exploratory structures' that work in close collaboration with outside entities and deploying reactive 'entrepreneurial units' to encourage the emergence of innovation and accelerate the marketing of innovative products."

Well, OK, then! I guess we'll have to wait some more for this fog to condense into something recognizable.

Devils, Metals, and Details

Tue, 30 Jun 2009 06:28:45 -0500

Organic synthesis as we know it can't go on without metal-catalyzed bond-forming reactions. There are too many of them, and they're just too useful. Palladium's the workhorse, followed by copper, then you've got rhodium, nickel, and a host of others (gold's been popular the last few years). We have a. . .fairly good idea of what's going on in these reactions, but not quite good enough. If we really understood all the factors involved, there wouldn't be six garbonzillion different sets of conditions for these things, would there?

A short paper's just come out in Angewandte Chemie that illustrates some of the trickiness involved. Carsten Bolm's group at Aachen has published several interesting iron-catalyzed coupling reactions using good old ferric chloride. These are aryl-amine, aryl-ether, aryl-amide and aryl-sulfide-forming procedures, which cover a lot of ground. (Interestingly, it was one of those sulfide papers that was recently plagiarized by another set of authors). But there were always a few kinks, such as variable yield depending on which bottle of ferric chloride was used.

Well, organometallic chemists are used to that sort of thing. But Bolm has gone back to look at things closely, in collaboration with Stephen Buchwald of MIT (whose group has published many similar couplings with other metal systems), and found a surprise. The iron chloride isn't doing a thing. In fact, as you go to more and more pure sources of the reagent, the yield drops off. But it never goes away, even with the 99.9% pure stuff. That's because it seems to be copper (I) contaminants doing the coupling, even at the parts-per-million level.

There are some startling tables in the paper. For coupling pyrazole onto an aryl iodide, for example, Bolm's group had found in 2007 that they could get 87% yield using >98% ferric chloride from E. Merck, along with dimethylethylene diamine as a cosolvent. If you use the >98% from Aldrich under the same conditions, though, you get 26% yield. And the Aldrich >99.99 stuff gives you only 9%. But if you add five ppm copper (I) oxide to that last reaction, the yield goes up to 78%. And if you leave the ferric chloride out completely, and just go with a trace of copper, the yield is exactly the same (it goes down if you run the same trace-of-copper without the diamine, which seems to be complexing it up into solution).

The other couplings that were reported seem to follow the same pattern. This must really be a disappointment to Bolm and his group, because their work was, among other things, an attempt to get away from copper and palladium. Still, this appears to be a much cleaner and more efficient copper reaction than a lot of the procedures out there.

This sort of thing has happened before in organometallic chemistry. There's a well-known example of nickel contamination in a chromium-mediated reaction from the mid-1980s, and more recently, a report of supposed "metal-free" couplings which appear to have been catalyzed by parts-per-billion levels of palladium found in the sodium carbonate being used as a base, of all things. Tricky things, these metals.

Eli Lilly Gives It Away

Mon, 29 Jun 2009 07:33:26 -0500

Not long ago, I wrote about a Pfizer program for smaller companies to come screen their targets against Pfizer's compound bank. Now Eli Lilly has flipped that around. In an initiative to bring other people's compounds out of the stockrooms and off the shelves, they'll screen them for free.

These aren't single-target assays. The company has four phenotypic screens going (for Alzheimer's, diabetes, cancer, and osteoporosis) and will look for improvement by any mechanism that comes to hand. No chemical structure information is shown to Lilly (I assume that they just know the molecular weight so they can run a dilution series). If something looks interesting, the company and the owners of the chemical matter have 120 days to come to terms for any further development deal - if not, then all rights revert to the submitter, and they can publish the data from the screens.

Lilly's working out a universal material transfer agreement, in collaboration with a number of universities, so that the paperwork stays the same every time. That's a good move. The lawyering can be a real holdup - in my experience, every party in these agreements usually comes in with slightly different wording in their magic legal spells, requiring several rounds of reconciliation before everyone's ready to sign.

I think that this is a worthwhile idea, and that they'll get a lot of takers. There are plenty of compounds sitting around in academic labs gathering dust, so why not send 'em in? The worst that can happen is nothing, and the best is that the compound actually turns out to be worth something. But will anything come out of it? The closest program to this is surely the National Cancer Institute's long-standing (since 1990) NCI-60 screening program, which also runs at no cost to the submitters. Even so, a recent reference mentions that there are between 40,000 and 50,000 compound in the NCI database, which actually seems rather small, considering. (To be fair, the program is not being funded at the levels that it was during the early 1990s). The only marketed compound that I'm aware of that can be said to have come out of the NCI-60 screen is Velcade (bortezomib), known then as PS-341, which was sent in for screening by Proscript Pharmaceuticals in the mid-1990s. Many other interesting structures have turned up along the way, though, which for various reasons haven't made it all the way through.

It'll be quite interesting to see what sort of hit rate Lilly's phenotypic assays call up - I hope they tell us. I have a lot of sympathy for the mechanism-agnostic approach myself, and I'd like to see how closely my bias are aligned to reality.