Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
One of the comments to yesterday's post turned the topic around by asking me how I like to be interviewed. That's a fair question, and I'm going to resist a quick answer of "In as fawning a way as possible". I have to say that I haven't been out on the conference-room trail in a few years - I'm not one of those people who goes out and interviews every couple of years just to keep their hand in. But I have been on the other side of the table a few times.
I think that one thing I look for is the quality of the questions I get asked. You want to join a company with good people, and what a person is curious about is a good window into how they think. That's one reason I'm not a fan of the mechanism-quiz technique, because at its worst it embodies some personality traits (bet-I-can-find-things-you-don't-know, test-until-destruction) that I find unappealing and counterproductive.
And that's why I don't necessarily mind getting questions that I don't know the answer to (as long as they're not questions that I obviously should know the answer to, naturally). It's good to be able to recognize anomalies and potentially interesting clues in a mass of data, so when someone picks out an oddity from a presentation of mine, I'm pleased (again, as long as it's one that I already knew about!) Many times, the answer to such questions is "Well, we don't actually know why that happens, but here are some possibilities. . ." The part of that answer after the comma needs to be included every time the first part is used, by the way.
I like seeing that the place I'm interviewing at is run in a reasonably organized manner. I'm not talking synchronized watches (which would make me run the other way), but if no one seems to have any idea of what my schedule is or where anyone can be found, it might be a bad sign for the way that projects are being run as well. (The flip side is that some apparent disorganization might be from everyone doing productive work instead, which isn't so bad).
And most of all, it's good to get the impression that people are doing things that they're interested in. At a small company, that's usually not a problem. But large companies have all sorts of people, and most places have some disgruntled time-servers taking up office space here and there. Any recruiting committee should know not to put these folks on an interview schedule. I've been on such committees myself, and you really do think about these things. So if I visit a place and end up talking to Wally out of the "Dilbert" strip, it's at best a mark against the people who made up my schedule, and at worst a bad sign for the whole department.
My "How to Get A Pharma Job" category over on the right has taken on a whole new meaning these days, what with me (and all my co-workers) scrambling around for new positions. You run into all kinds of interviewing styles out there, most of them fairly benign - but there are a few techniques that (to me, anyway) are warning signs.
The "Let's Go to the Board" folks can be in this category. (I've spoken about this before). While it's true that you want to make sure that a prospective candidate understands the science of what they're doing, a dissertation-defense blackboard grilling may not be the best way to do that. A medicinal chemists's job does not, to a first approximation, revolve around solving mechanism problems. It's a useful skill, and can be used as a surrogate for general mental acuity, but it's not the absolute first requirement.
At the other end of the scale, you have the HR-department "If you were a tree, what kind of tree would you be?" interviewers. I should point out that the people who ask these sorts of questions generally aren't the shining stars of the HR office themselves. And yes, I actually have heard of someone getting the tree question. I live for the day that someone tries it out on me.
People who have been through a lot of training courses may also try out a technique called "Behavioral Event Interviewing". That's when they ask you about some situation you found yourself it - "Tell me about a time when you had to meet a tight deadline", or the like. There's nothing wrong with this in principle, but if it's the centerpiece of the whole interview process, I think that it turns into a moral hazard for the interviewee. That is, it's an incentive to bring out the makeup crew and the special effects team, for a new, improved, version of the past. Everyone does this to a degree, of course, but the BEI style almost encourages it.
And it should go without saying that if you're treated in a disrespectful manner during an interview, and it seems like part of the company culture rather than the work of a random fool, then you should keep on walking. This is rare, but it happens. I knew an associate a few years ago who got a call for a Saturday morning interview at a small company, which was done by several of the lab heads who sat around eating breakfast in front of her. Do you really want to work for a company that thinks that this is acceptable behavior? Exactly.
So, what actually happens, down at the molecular and cellular level, when a person is exposed to alpha radiation? If it’s coming from outside the body, not all that much. The outer layer of dead skin cells is enough to soak up most of the damage, and it’s not like alpha particles can make it that far through the air, anyway. This is good news for Londoners worried about exposure (I note that reports have at least three sites there showing traces of radioactivity). I strongly discourage anyone from standing around next to an alpha source, but there are a lot worse things that you can stand next to - a gamma or fast neutron source, for example, either of which will penetrate your tan and keep on going.
But inside the body, that’s a different story. Alexander Litvinenko was given polonium in his food or drink, and from there the stuff distributes fairly widely across many tissues. At lower radioactive doses, that pattern is probably a good thing. When you have a radionuclide that concentrates in a particular tissue, like iodine in the thyroid, a dose that would be bearable across the entire body can cause a lot of local damage when it piles up. At higher doses, though, the situation can flip around. People can survive with damaged thyroid glands, or after total bone marrow transplants or the like. But general tissue damage is much harder to deal with.
Polonium ends up concentrating in the kidneys, to the extent that it concentrates anywhere, and attempts have been made to minimize radiation damage there. But by then an awful lot of destruction has occurred elsewhere – the blood-forming tissues, the linings of the gastrointestinal tract and the blood vessels themselves, and others. Note that these are all fast-dividing cell populations.
Zooming in, the mechanisms for all that mayhem are complex, and they’re still not completely understood. The first thing you can imagine is the alpha particle smacking into something, which to a first approximation is exactly what happens. They don’t get far – less than 100 micrometers. But along the way they can bash into quite a few things, losing some energy each time, which shows up as flung-off electrons, various strengths of photons, and doubtless some good old kinetic bouncing around. Eventually, when the particle slows down enough, it drags off a couple of electrons in passing and settles down as a peaceful atom of helium. That leaves some positive charges to account for, though, since those electrons were otherwise employed before being press-ganged, and this ionization (along with that caused by those stray electrons along the way) is one of the major sources of cellular damage.
All this can take place either in the nucleus or out in the cytoplasm, with different effects. This sort of thing can damage the cell's outer membrane, for one thing, which can lead to trouble. In the nucleus, one of the more dramatic events is sudden double-strand DNA breakage. That's never a good thing, since the strands don't always get put back together correctly. A couple of years ago, a group from the Netherlands was able to come up with dramatic images of chromosome breakage along the tracks made by alpha particles in living cells.
Then there’s also the complication of the “bystander effect”. Untouched cells in the vicinity of one that has taken an ionizing radiation hit also show changes, which seem to be at least partly related to an inflammation response. This seems to happen mostly after damage to the nucleus.
All this focused destruction has long since drawn the attention of people who actually want to kill off cells, namely oncology researchers. Alpha sources conjugated to antibodies are a very big deal in cancer treatment, and a huge amount of work is going on in the area. The antibodies can, in theory, deliver the radiation source specifically to certain cell types, which soak up most of the exposure.
So there's a use for everything. But one of those uses, this time, was assassination. Alexander Litvinenko's killers knew exactly what they were doing, and exactly what would happen to him. I hope that they're eventually found and dealt with proportionately.
I was going to write up a piece on thallium poisoning, until word came out over the long weekend that the Russian spy case was instead an instance of polonium poisoning. That's a very different matter indeed.
For starters, polonium isotopes (like most radioactive substances) are much more hazardous as radiological agents than as chemical ones. Unraveling the two isn't always easy, but this case is pretty clear. It's likely that polonium is chemically toxic, since it's in the same series as selenium and tellurium (which both are), but it's also likely that any reasonable dose would kill a person from alpha radiation rather than from whatever enzyme inhibition, etc., that might also ensue. People have been dosed with fairly robust amounts of tellurium and survived, albeit uncomfortably, but I can't imagine that anyone has been exposed to a systemic dose of a hard alpha emitter and pulled through.
This takes us into the long-standing arguments about the toxicity of such isotopes. Readers who remember the anti-nuke days of the 1970s and 80s may recall the statements about plutonium's incredible toxicity, generally expressed in terms of how miniscule an amount would be needed to kill every human being on the planet. Left unsaid in those calculations was that said plutonium would have to be dosed intermally in some bioavailable form. More Pu was surely vaporized in the atmospheric bomb tests of the 1950s, without depopulating the Earth to any noticeable extent. (See the arguments here, for example).
Here, though, we have a case of that exact bioavailable dosing of a strong radioisotope, with the unfortunate effects that you'd predict. There were some experiments early in the atomic research era where patients were dosed with radioactive isotopes. Oddly, the polonium experiments may have been the only ones that stand up to ethical scrutiny. A good review of what's known about polonium exposure, at least as of 1988, can be found here.
One thing that many people may not realize is that every person on the planet has some polonium exposure. There are many people who equate "radioactive" with "man-made", but those categories don't completely overlap. Polonium is a naturally occurring element, although certainly not in high abundance, but there's enough for Marie Curie to have isolated it. It's part of the radioactive decay series of U-238, and as a daughter radionuclide is a contributor to the toxicity of radium and radon exposure. You've had it - but not like this.
Another thing a large research site has, and in mighty impressive quantities, is paper. Something's got to be done with it, but not all laboratory paper is created equal.
Of course, a lot of the mass represents hard copies of files that exist in digital form. Non-proprietary stuff (journal articles that are no longer needed, etc.) will go into big recycling bins to be handled by guys who really have some long days ahead of them. A serious office move (and this is about as serious as it gets) is a good chance to toss ancient literature folders whose contents have become outdated. I just heaved out a pile of that stuff the other day, since I don't thing that 1991 reviews of Alzheimer's pathology are going to come back into fashion. I also had a bunch of miscellaneous hard copies of the Journal of Organic Chemistry from the early 1990s stuffed into a file cabinet - out they went. They were joined by old copies of C&E News, local phone books, 3-ring binder contents of short courses whose contents I don't expect to ever need, and a pile of chemical company and lab equipment catalogs.
Pages with proprietary data on them are a different matter. They're to be tossed in a special shredder box, to be picked up later by some other guys who are also going to earn their money. There are trailer-size portable shredder operations that you can hire for occasions like this. Compound lists, graphs of in vivo activity, photocopies of notebook procedures, handouts from project meetings - all that stuff is headed down this path. Different people save different amounts of this material. I save all the computer files, but heave most of the paper when a project finishes up, so I don't have as much in this category.
Things like printed NMR spectra used to be in a special category, because back in the days of expensive digital storage the hard copy was all you had. I guarded my NMR spectra pile fiercely in grad school, since I was going to need that data to get out of there. And in my first years in the industry, digital archiving was spotty. Now that gigabytes are carried around on key chains, all spectral data are automatically archived, so hard copies are just a convenience.
At the top of the paper mountain are lab notebooks. We switched over to an electronic notebook system a few years ago, but it didn't relieve us of the obligation of keeping a hard copy. Printouts are to be taped into the good ol' notebooks, and signed and witnesses just like the handwritten pages of yore. That's a legal requirement, and scientists at research sites across this great nation are regularly harangued about keeping up to date on it. It does little good. Researchers are just not wired to get things countersigned on a regular basis.
That can lead to some real problems for US patents in particular. We're still a "first to invent" country, while the rest of the world is mostly "first to file". And if you get in an argument about the date of an invention, well, lab notebooks are probably where you're going to end up. An invention that isn't signed and witnessed until a year or so later isn't going to help much in that situation. Admittedly, it's rare that things get to that point, but when they do it means that serious money is at stake.
So no one's throwing away any notebooks, that's for sure. And we're all getting them up to date, signed off on, etc. Companies keep track of every extant lab notebook - they're all numbered, and completed ones no longer in immediate use are kept under lock and key. Nothing's going to be allowed to slide.
Since I mentioned a little while ago that I'd gone short Imclone stock (at $29 and change), it was heartening to see Gretchen Morgensen make the exact same case against them in the New York Times on Sunday. (Subscriber link). The article makes much of the company's recent patent troubles, and the competition for their lone drug, Erbitux:
But neither the new competition from Amgen nor the legal ruling on the Yeda matter seems to worry the hopefuls who have bid up ImClone shares in recent weeks. These speculators also appear undaunted by results earlier this month from a drug trial in patients with midstage colorectal cancer. ImClone had hoped that the trial would show a survival benefit; it did not.
Two analysts, at Merrill Lynch and Citigroup, predicted that the trial results would mean stagnant market share for Erbitux and growth prospects for Vectibix. Both analysts rate ImClone a “sell.” Bristol-Myers Squibb, which owns 17 percent of ImClone, said in its most recent quarterly filing that Yeda might seek damages for infringement on past Erbitux sales and royalties on future sales of the drug. If Yeda licenses its patent to other companies, Bristol-Myers acknowledged that new competition for Erbitux would arise, but added that it was too early to tell what impact such a development would have on its business.
Investors are going to have to catch up with therapeutic reality here: Erbitux is a drug of limited utility. All cancer drugs are, unfortunately. "Cancer" is a catch-all term for hundreds of distinct disorders of cell division and growth, and no one drug is likely to be efficacious across much of that range. Even in its best applications, though, Imclone's drug is only fair-to-good. Meanwhile, progress in the field (though incremental) is very real, and every slightly better compound that comes along is going to capture a lot of market share.
So when I hear Carl Icahn going on about how he wants the company to step up its marketing efforts, I have to roll my eyes. The thing is, to some extent cancer drugs market themselves. They already sell much more than a purely rational calculation would predict. That's because many clinicians try them all, against all sorts of things, no matter what the label says. And it's not like no one's heard of Imclone or Erbitux, so there's only so much that a whiz-bang selling campaign can accomplish. Icahn is trying to apply the lessons he's learned from other industries to pharmaceuticals, a tempting idea that has sent more than one R&D-based organization rolling off the edge of the table.
I know that I've linked to this post of mine several times - it's the one where I talk about all the times I've told people to sell Imclone. But you know, it's been good advice. After all, I took it myself, and I didn't even own the stock. . .
OK, here's a stumper: are there any anti-inflammatory medications that don't have cardiovascular side effects? Aspirin's GI bleeding effects have been known for decades, various NSAIDs have had warnings turn up over the years, the COX-2 drugs are somewhere over there in that huge cloud of legal and statistical dust, and now a study says that one of the last left standing, naproxen, may have cardiac effects as well.
Or does it? This is an attempt to get some useful data out of a large Celebrex trial, looking to see if it had protective effects against Alzheimer's disease, and the whole thing was stopped early when all the COX-2 cardiovascular risks became an issue. As this article makes clear, Steve Nissen isn't convinced, and he's not a person who keeps his worries about drug safety all bottled up inside. His point is that the trial's statistical validity was ruined by the early halt, and that larger epidemiological studies don't back up its conclusion. I should note that he's now running a massive trial addressing this issue as well.
Contrast that with this quote from one of the new paper's authors:
"Particularly for safety data, 'truth' may come in small doses. We firmly believe that results from trials should be published regardless of the direction, magnitude, or statistical significance of the observed results," said Barbara Martin of the John Hopkins University School of Public Health, who worked on the study.
Let me tell you, that kind of thing makes me very nervous. Regardless of the magnitude or statistical significance? That's not a way to arrive at the truth. That's a tornado passing over a pig farm
As I mentioned the other day, I'm sprinting to finish some last experiments on my side project. These are all on the "vial thirty-three" system that I first described here and finally got to work reproducibly here. Looking back, I remember how surprised I was earlier in the year when I first saw this experiment work. Figuring it out has been like building an invisible ladder and then climbing up it, watching the rungs become solid under my feet.
Now, of course, I'm pulling out all the stops there are to pull. There are so many other experiments that I've been planning for and trying to do, but they won't get done, at least not here. I have to do everything I can with what I have on hand, because there's no time to make anything new. The publication that comes from this won't be as sweeping a story as I'd like for it to be, but it'll do.
But I'm accomplishing more in a few days than I have in months, because, sadly, there's no one competing for any of resources I need. Compounds from the repository? They're ready inside of an hour. More biological materials from the labs in the next building? They're giving me whatever I want, because all the projects that had first call have been stopped. The mass spectrometer downstairs, an essential piece of equipment for me and the largest single bottleneck I've faced? It's wide open as of tomorrow. I don't have to get in line any more; there is no line.
I went downstairs and loaded up one of the NMR machines with a day-long queue of proton and carbon spectra - in fact, they're still going and they'll be running all night. If I'd pulled that a month ago, someone probably would have gone out to the parking lot and slashed my tires. Now I'm the only person using the machine at all. No one cares. This brief, strange interval has been like having my own research institute, and I doubt if I'll ever see anything quite like it again. Everything's going perfectly, because everything's going away.
When a bunch of chemistry projects suddenly stop in their tracks, you're faced with a real waste disposal problem. What do you do with all the blasted chemicals? First off, there are reactions going in people's fume hoods, some of which probably aren't going to be worked up. Into the red waste can they go. Then there are all the opened bottles of solvent, which aren't going to be shipped off anywhere like that. Unless there's a local university that's not very picky, those are going to end up hauled off for waste, too. (I wouldn't trust a solvent bottle that someone unknown to me has opened and left around, personally, especially if I have no way of tracking down its previous owner).
Solid commercial reagents are a bit different, since they're generally more stable and less likely to be contaminated (and often easier to spot if they've gone bad). Everything unopened - and every lab has plenty of unopened stuff in it, for one reason or another - will either be moved to the sites that are still running, or have several chances at donation or sale before being treated as waste. Opened commercial reagents will be subject to the same calculations, but on a steeper curve. Is the stuff still commercially available? Do the folks on the other end have enough of it already? If no, is anyone likely to want it? Is it worth shipping a long distance? Any "no" answers send the bottle to the "donate" pile, and that much closer to a waste pickup.
My guess is that very few of the commercial reagents will stay within the company. Compounds and intermediates that were made in-house, though, will get much more deferential treatment. These are almost certainly not commercially available, and have (be definition) been used to make something that was thought to have some value and to have some chance of being proprietary. Everything in this category will probably make the cut for being shipped, unless it's obviously turned to black tar on storage.
The mother lode of these compounds is, of course, the repository. Every drug company has one, full of racks and rows of vials and small bottles, every one of them containing something that someone thought was worth making and worth testing. Some of these have been dissolved in small quantities of DMSO, for liquid handling machines to dispense them, and these may or may not be worthwhile. But all the stock solids will be carefully packed and shipped off, no questions asked. They represent a huge investment in man-hours and money. Tossing them would be like a coal company setting its mines on fire.
Just a few days after I commented on the troubles that Isis Pharmaceuticals has had developing antisense DNA therapies, they've popped up with impressive clinical cardiovascular clinical data. Their latest hope, ISIS 301302, has shown some strong LDL-lowering effects, both as a single agent and in combination with statin therapy.
It's aimed at the production of a key LDL-transporting lipoprotein, apoB-100, which target the company correctly describes as "undruggable" through standard med-chem approaches. Of course, the RNA people are hot on its trail, too (these guys, for example). It's a good opportunity for these approaches, since the protein is of clear biochemical importance, and the site of its synthesis is in the liver and gut wall. Those, of course, are the first tissues that an oral drug sees, and (in the case of many antisense and RNAi attempts) the last ones, too. Going after something that lives there is a good strategy.
On a different topic, welcome more additions to the blogroll, such as Totally Medicinal, a med-chem blogger who's concentrating on the synthetic chemistry end of things. And there's Xcovery, a good kinase-o-centric site for those who can't get enough of 'em.
We now return you to our regularly scheduled site closure, already in progress. I've started a new category, "Closing Time", where my posts on that topic will go. There are a lot of odd blogworthy issues and loose ends associated with shutting down an operation like this. I'll be writing on them in the coming weeks, since many people will (fortunately) not have experienced the process firsthand.
Friday afternoon was quite strange. There had been another meeting to explain to people what the timetable would be to close down the site, but I left during its question-and-answer period. . .to go and set up an experiment. A half an hour later, colleagues of mine from down the hall were coming back from the main auditorium, talking among themselves about job searching and severance, and staring at me in disbelief as they walked past my lab bench.
You see, if I'm going to get a good publication out of my idea, I'm going to need some more data. For one thing, I need to go back and run some of the things I've already done, but this time at least in triplicate, so I can plot the data with error bars. Before I was running in duplicate, trying to save some of the harder-to-obtain reagents for later experiments, but that's not going to be an issue now. Inside of a couple of weeks, there aren't going to be any more experiments to run, because we're going to be shutting down the labs.
In addition to the repeats, I'm going back to my main sequence and setting up some new experiments which will help support my conclusions in a paper. Friday afternoon's run was a large one in that category, and (needless to say) it had better work. I'm not going to get much time to troubleshoot. I had been working on a different series of compounds, but there's not going to be time to finish that area, so it has to be thrown over the side.
So there I was, using some pipets that were left over when the company laid off a hallway full of biologists two years ago. I have no idea who the equipment I'm using belonged to, but I knew everyone over there. And the vials I set up went into a plastic rack, which is still labeled with the name of a lab associate who was let go about a year ago when another hallway was cleared out. I'm using reagents from projects that have been told to stop, trying to generate data before the analytical lab has to shut down. No wonder people were looking at me as if I'd lost my mind - if I had the time, I'd stop and stare, too.
It's not my intention to turn the site into a Saga of the Job Hunt, although that will be a recurring subject for a while. (I'd like to thank everyone for their expressions of support in yesterday's post, by the way. Much appreciated). The immediate future is fine - I'll still be at the workplace into December, and my lovely-parting-gifts package from the Wonder Drug Factory looks like it can take me a good way into next year if needed.
One interesting side effect of all this has to do with the side project described (elliptically) in the Birth of an Idea posts. Weirdly, the rapid end of normal research work at my site has opened a window of opportunity to get some of my off-the-radar samples looked at, and I plan to take advantage of that. I'm setting up a good-sized run of experiments to go over this weekend, for example.
I also hope to write up these results as quickly as possible, and for a better journal than I've appeared in to date. So here's a question: which journal? I think that this has a good shot at Angewandte Chemie or JACS, but I'm also considering really going for broke and sending it somewhere like Science or Nature. Can anyone speak to the reception that organic/medicinal chemistry manuscripts get in these venues? And are there other places I should consider (PNAS, for instance)? I realize that it's hard to judge this sort of thing without knowing quite what the manuscript is about. . .
Well, here's a post I didn't think I'd be writing, although the possibility (given my industry) has always been there. The Wonder Drug Factory has decided to totally rearrange their research divisions, and we've been informed that our site is slated to close. Several hundred people will be losing their jobs, and I'm one of them. I don't agree with the decision (hey, I never think it's a good idea to turn me out on the street), but "out of my hands" doesn't begin to describe it. By all appearances, things will be shut down by the end of the year.
So the job search is on, and I'm going to start it by using whatever size platform I've built here. As for my background and experience, well, si curriculum vitae requiris, circumspice. I'm told by colleagues that reading my site is a pretty good simulation of having me around in person, so (for better or worse), that's what you'd be getting. I can provide a more traditional CV on request, of course, with the accompanying lists of patents, publications, and previous projects.
For family reasons, I'd prefer to stay in Connecticut, but I'll obviously start looking farther afield depending on what's out there. Industrial drug discovery is my strong point, naturally, but I'm certainly willing to listen to other ideas (academia, etc.) I can be contacted at firstname.lastname@example.org. I also want to mention that I have a number of very capable colleagues, at all levels of experience. Recruiters and search firms, give me a call - I can put you on to some excellent prospects: chemists, biologists - we've got 'em all. Or more accurately, we had them all, until today.
I'd been reasonably optimistic as the clouds gathered here over the last few months, but at the same time I've been preparing for this event, which is within error bars of the worst case. As for my attitude toward such things, I can tell you that Epictetus said it a long time ago:
Work, therefore to be able to say to every harsh appearance, "You are but an appearance, and not absolutely the thing you appear to be." And then examine it by those rules which you have, and first, and chiefly, by this: whether it concerns the things which are in our own control, or those which are not; and, if it concerns anything not in our control, be prepared to say that it is nothing to you. . .
When therefore we are hindered, or disturbed, or grieved, let us never attribute it to others, but to ourselves; that is, to our own principles. An uninstructed person will lay the fault of his own bad condition upon others. Someone just starting instruction will lay the fault on himself. Some who is perfectly instructed will place blame neither on others nor on himself.
Losing this job has not been in my control. Finding another one is. Here goes!
As many of you have noticed, there's some Movable Type construction work going on behind the scenes over here, which seems to have knocked out the commenting function for the moment. I hope that it'll be back quickly, and that the various service interruptions will diminish.
I was up late eating Indian food and following the election, with little time to post last night. No matter which side you were cheering for, I can recommend plenty of tandoori chicken and papads. My wife's home-made basmati rice, curried cauliflower, and cucumber yogurt are not (as of yet) available online, though, so you're on your own there.
One of the things I like most about science is that you really don't know what's going to happen next. That's especially true in the areas where things have just barely settled down. Before that, when a field is new, no one knows what to expect, so in a way there aren't really any surprising results: everything's a surprise. A much more settled area, by contrast, is far less likely to produce surprises, although when one shows up it really stands out. But a field where people are just starting to exhale and think that maybe they've finally figured out what's going on - that has the best combination of high contrast and a real likelihood for craziness.
Here's a perfect example, since I was just expressing some doubts about the immediate commercial potentials of RNA interference the other day. In a paper coming out in PNAS, a group at UCSF was investigating the use of some small double-stranded RNAs, just the sort of thing that can be used for RNAi experiments. But they found (to their great surprise) that their experiments were stimulating the transcription of their targeted genes, rather than shutting them down. Needless to say, this was not what anyone expected, and I'll bet the folks involved repeated these things many, many times before they could trust their own eyes. There are plenty of other people who won't believe it until they've seen it with theirs.
On a molecular biology level, it's hard to say just what's going on. The authors, according to this news item from Science (probably subscriber-only) say that they've found some rules about which genes will be susceptible to the technique and which won't, which will be released soon. (Translation: as soon as they can be reasonably sure that they won't make fools of themselves - this paper took enough nerve as it is).
The Science article includes a good deal of if-this-holds-up language, which is appropriate for such a weird discovery. (Are the editors there wondering why they didn't get a chance to publish the article themselves, or did they have the chance and turn it down?) At any rate, if-it-holds-up this effect will simultaneously complicate the RNAi field a great deal (it was gnarly enough already, thanks) and also open a door to some really unusual experiments. Upregulating genes isn't very easy, and there are no doubt many ideas that have been waiting on a way to do it. There are therapeutic possibilities, too, naturally - but they'll have to wait on the same difficulties as the other RNA therapies.
Anyway, I'm happy to see this. It opens up some completely new biology, and it opens a door to a potential Nobel for the discoverers should everything work out. And it always cheers me up when something totally unexpected flies down like this and lands on the lawn.
If you're one of my industrial-research readers and you're looking for a trend to get worried about, try this one: the number of large companies that are opening med-chem research sites in China. Here's the latest example, from Novartis, and it might be the biggest yet.
There's a huge expatriate Chinese research presence in the US and Europe, and has been for many years. Recently, though, some of them have been moving back to China (or, probably, not leaving at all) because of the opportunities that have opened up there. As with other industries, it started out as we'll-do-your-worst-stuff contract work, and has picked up from there. Now we're to the point where companies can consider doing serious med-chem.
To a first approximation, I guess I'm supposed to be upset about this. But (free-trader that I am), I remember that at one point the US was the offshore research location for European firms. And as China's economy develops, those low-wage jobs that attract this kind of outsourcing won't stay so low-wage. If you're a worried US or European researcher, you pretty much have to hope for China to grow and take off to that point, or you have to root for a collapse. I vote for the former.
Another reason I'm not worried is that research isn't a zero-sum game. There are more pharma ideas to work on than anyone has time, manpower, or money to investigate - there always have been, and there will be for some time to come. Now, not all of these are going to be great ideas. Most of them are going to flop. But there's not much way of knowing which ones those are, so having a chance to put more bets down is a good thing.
"Ah, but research budgets are zero-sum", I hear some of you saying. That's a better point, but I don't see (yet) any evidence that these offshore operations are being used to substitute for current operations. As far as I can tell, they're in-addition-to, on the cheap. After all, no one's sure yet how well these things will work out, especially in these early cases, and given the state of the industry, cutting your research back hard is not a very good decision.
But yes, the competition is there, and will be increasing. As I've said here before, that means that you have to try to offer something that a company can't get in Shanghai. And sitting around wringing your hands about China (and India) instead of coming up with good ideas or improving your skills isn't going to do that.
I haven't mentioned Merck's mighty acquisition of Sirna yet - 1.1 billion dollars, eh? If anyone didn't think that RNA interference was hot, that kind of money should change their mind.
But still. . .antisense DNA was hot at one time, too, and then it cooled off considerably. It's come back in recent years, admittedly, as painful progress has been made. In fact, one of the big deals that showed that antisense was taken seriously again was made by. . .Merck, come to think of it. They had a big collaboration with ISIS for diabetes and (I believe) some other indications, but it didn't work out well. That press release has ISIS putting a brave face on having their clinical candidate thrown back over the fence, with talk of taking it on into clinical trials themselves. Four years later, it's still listed as Phase II on the company's website, which isn't a good sign, I think.
The rest of that 2002 press release is also instructive. The Phase III PKC-alpha compound they mention working on with Lilly bit the dust the next year, for one thing. And the ICAM-1 inhibitor met a similar fate in 2004. The 2002 story mentions the company having six products in Phase II, and now, according to their chart, they have five. None of those six candidate have progressed, and no doubt there's been some turnover along the way.
I'm not trying to be hard on ISIS. It's just that antisense DNA therapies have been extraordinarily hard to develop, and I see no reason why RNA interference will not have exactly the same sorts of problems. Small nucleic-acid based compounds are going to be hard, no matter what. It's interesting to note that Merck didn't just up and buy ISIS back then. But they're more desperate to fill their pipeline than they were back in the late 1990s, so out comes the checkbook. Good luck to all concerned.
Back in 2003, I wrote about the paper that identified the natural product resveratrol as an activator of the sirtuin deacetylase pathway. This may well be the common thread between a host of studies on life-extending genes in model organisms and the much-publicized phenomenon of life extension through caloric restriction. In other words, if you want to live longer, but don't feel like taking in a third fewer calories, it's possible that activating sirtuin might do the job for you, and resveratrol is the prototype activator.
Three years ago, after first pointing out that many companies might want to run screens for sirtuin activators, I went on to speculate:
Second, there is no reason to think that resveratrol itself is an optimized molecule. It's a great starting point, but as a medicinal chemist I can see several things I'd like to do to it immediately. Hey, fellow chemists, let's talk shop here. . .(list of possible structural modifications follows - DBL). . .Believe me, thousands of folks like me are looking at this structure today and having these exact thoughts, and some of them are going to act on them (if someone hasn't already.)
Third, this compound is surely being given to higher animals as we speak. I can see no reason not to start feeding it to mice in a long-term study. Mice live around two years - let's try for three! After all, it's already been given to rodents in other studies. (And those are just papers from the last year or two!) But as far as I can tell, none of these have allowed the mice to age to their full normal lifespan under resveratrol dosing. Time to find out!
Well, in an unusual development for my predictions, all of this is coming true. This summer, David Sinclair (who leads one of the major efforts in this area - another is led by his former boss, Leonard Guarente) published an interesting review of resveratrol's in vivo effects. Now his group reports in Nature that resveratrol does indeed have effects in mice - very powerful effects indeed. When put on a high-fat diet, normal mice gain weight, develop diabetes and liver problems, and die early. But on the same diet along with resveratrol, the mice (although they do put on weight) show improved glucose and insulin levels, better liver function, and significantly increased lifespan. Their activity and motor abilities appear to mimic normal-diet mice, even into their extended old age. (Here's their press release if you don't have a Nature subscription).
And on top of this, Sinclair's company has let it be known that they have developed improved molecules based on resveratrol, and are now taking them into the clinic. The first one is called SRT501, and I'd be very interested to know its structure. But remember that compound code - you're going to be hearing about it again.
These are still early days. There may be penalties to pay for messing around with longevity (increased cancer rates are only the first thing that come to mind). But there may also be a revolution in progress here, something that will make the future quite different from what we've been imagining it will be. G. K. Chesterton would be happy - scroll down here for a discussion of the game of "Cheat The Prophet". Is anyone ready for Cheat the Reaper?
The German government has handed down some interesting pharmaceutical decisions recently. Although Sanofi-Aventis's Accomplia (rimonabant) is available there (in fact, that's probably the largest market it's shown up in so far), the German regulators have decided that state health care plans are not going to reimburse for it. They've put it in the "lifestyle" drug category, which they don't cover. This appears to be a cost-cutting move, and there's a 60-day window in which it can be changed.
S-A had better hope that HMOs here don't follow suit. Of course, for this to be an issue, the drug would actually have to be approved by the FDA here, and the company still has no details to offer about when they might expect that. Their quarterly report states that they've answered the FDA's concerns, which isn't much of an update, but goes no further, as far as I can see.
Meanwhile, Pfizer's inhaled insulin Exubera has also been denied reimbursement in Germany, which follows on a similar British decision earlier. I expressed doubts about the product here a while ago (I wasn't alone), and now the doubters are getting louder. Exubera hasn't been launched in the US, either, despite being approved early this year, which isn't helping sooth Pfizer's hardy investors, either. . .
Presumably both these products will debut here in 2007, and we can all see how they do in the most lucrative pharmaceutical market in the world. If anyone is thinking of making a big upside investment decision based on these compounds, though, I think they'd be well advised to sit on their money for a while.