About this Author
College chemistry, 1983
The 2002 Model
After 10 years of blogging. . .
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: email@example.com
April 30, 2010
In case anyone missed it, a commenter on this post unearthed a really extraordinary find in the chemical literature. Here's an obscure isolation paper, from an obscure Chinese journal, reporting on a profoundly boring list of marine natural products.
What's so great, you ask? Well, take a look at the list. Dum de dum. . .hold on a minute, bis(2-ethylhexyl) phthalate? From Streptomyces, you say? When it's one of the most common plasticizers in the world, a bulk industrial chemical that, well, notoriously leaches out of labware under solvent exposure? Sure thing, guys. Sure thing.
+ TrackBacks (0) | Category: How Not to Do It
I'm working on breaking out the "Rate The Chemical Supplier" posts into a separate area for reference. But here's another interesting contribution in that area. This paper looks at several of the big compound-library suppliers, and evaluates their collections based on compound uniqueness, physical properties, etc.
The take-home? Suppliers seem to have paid more attention to making unique compounds over the last few years, in attempts to stand out from the herd. The percentage of compounds with roughly drug-like properties has increased a bit since 2006 (with Enamine running high and SALOR running low), although the ones with lead-like properties (smaller, etc.) has gone down a touch over the same period (Chembridge and Enamine are probably two of the best in that regard). And the different suppliers actually vary quite a bit in the diversity of their collections: Life Chemicals and AMRI, for example, tend to have larger clusters of similar compounds, while Peakdale and Oakwood have many more singletons. (Whether these are bugs or features depends on what you're looking for). If you're buying large numbers of diverse compounds for screening, the paper's definitely worth a look.
+ TrackBacks (0) | Category:
Many readers will have heard of Rosetta@Home. It's a distributed-computing approach to protein folding problems, which is certainly an area that can absorb all the floating-point operations you can throw at it. It's run from David Baker's lab at the University of Washington, and has users all over the world contributing.
A reader sends along news that recently the project seems to have come across a good hit in one of their areas, proteins designed to bind to the surface of influenza viruses. It looks like they have one with tight binding to an area of the virus associated with cell entry, so the next step will be to see if this actually prevents viral infection in a cell assay.
At that point, though, I have to step in as a medicinal chemist and ask what the next step after that could be. It won't be easy to turn that into any sort of therapy, as Prof. Baker makes clear himself:
Being able to rapidly design proteins which bind to and neutralize viruses and other pathogens would definitely be a significant step towards being able to control future epidemics. However, in itself it is not a complete solution because there is a problem in making enough of the designed proteins to give to people--each person would need a lot of protein and there are lots of people!
We are also working on designing new vaccines, but the flu virus binder is not a vaccine, it is a virus blocker. Vaccines work by mimicking the virus so your body makes antibodies in advance that can then neutralize the virus if you get infected later. the designed protein, if you had enough of it, should block the flu virus from getting into your cells after you had been exposed; a vaccine cannot do this.
One additional problem is that the designed protein may elicit an antibody response from people who are treated with it. in this case, it could be a one time treatment but not used chronically.
The immune response is definitely a concern, but that phrase "If you had enough of it" is probably the big sticking point. Most proteins don't fare so well when dosed systemically, and infectious disease therapies are notorious for needing whopping blood levels to be effective. At the same time, there's Fuzeon (enfuvirtide), a good-sized peptide drug (26 amino acids) against HIV cell entry. It was no picnic to develop, and its manufacturing was such an undertaking that it may have changed the whole industry, but it is out there.
My guess is that Rosetta@Home is more likely to make a contribution to our knowledge of protein folding, which could be broadly useful. More specifically, I'd think that vaccine design would be a more specific place that the project could come up with something of clinical interest. These sorts of proteins, though, probably have the lowest probability of success. The best I can see coming out of them is more insight into protein-protein interfaces - which is not trivial, for sure, but it's not the next thing to an active drug, either.
+ TrackBacks (0) | Category: Biological News | Drug Development | Infectious Diseases
April 29, 2010
I'm not sure how to interpret this, but my wife just sent me this link. She points out that the item is not only on sale, but that I can get free one-day shipping. Time, however, appears to be running out on that last option, so I must (yes!) act without delay.
I'm thinking of counteroffering with a different allotrope. I'll let everyone know how that goes.
Update: her latest offer is an equitable 50:50 deal - I buy her the ring, and she gets the graphite rod for me. That plan is, I think, that this way I get the shaft twice.
+ TrackBacks (0) | Category: Blog Housekeeping
In keeping with the problem discussed here ("sticky containers"), there's a report that a lot of common spectrometric DNA assays may have been affected by leaching of various absorbing contaminants from plastic labware. If the published work is shown relative to control tubes, things should be (roughly) OK, but if not, well. . .who knows? Especially if the experiments were done using the less expensive tubes, which seem to be more prone to emitting gunk.
We take containers for granted in most lab situations, but we really shouldn't. Everything - all the plastics, all the types of glass, all the metals - is capable of causing trouble under some conditions. And it tends to sneak up on us when it happens. (Of course, there are more, well, noticeable problems with plastics in the organic chemistry lab, but that's another story. Watch out for the flying cork rings!)
+ TrackBacks (0) | Category: Biological News | Life in the Drug Labs
Here's something I never knew: odors can regulate lifespan. Well, in fruit flies, anyway - a group at Baylor published results in 2007 showing that exposure to food-derived odors (yeast smells, in the case of Drosophila) partially cancels out the longevity-inducing effects of caloric restriction. Normally fed flies showed no effect.
That 2007 paper identified a specific sensory receptor (Or83b) as modulating the effect of odor on lifespan. Now comes a report that another receptor has been tracked down in this case, the G-protein coupled Gr63a. Flies missing this particular olfactory GPCR no longer show the lifespan sensitivity to yeast odors. This narrows things down. Or83b mutations seem to broadly affect sensory response in flies, but this is a much more specific receptor, just one of a great many similar ones:
"Unlike previous reports involving more general olfactory manipulations, extended longevity via loss of Gr63a occurs through a mechanism that is likely independent of dietary restriction. We do, however, find that Gr63a is required for odorants from live yeast to affect longevity, suggesting that with respect to lifespan, CO2 is an active component of this complex odor. Because Gr63a is expressed in a highly specific population of CO2-sensing neurons (the ab1C neurons) that innervate a single glomerulus in the antennal lobe (the V glomerulus), these data implicate a specific sensory cue and its associated neurosensory circuit as having the ability to modulate fly lifespan and alter organismal stress response and physiology. Our results set the stage for the dissection of more complex neurosensory and neuroendocrine circuits that modulate aging in Drosophila. . ."
It's going to be very interesting to follow that neuronal pathway - I've no idea where it will lead, but we're bound to learn something worthwhile. To make a wild generalization straight up to humans, this makes me wonder about people who are practicing caloric restriction on themselves - they're still exposed to food odors all the time, right? Does the same reversal apply? For me, I think that the scent of barbecue and fried catfish might be enough to do it right there, but keep in mind that I'm from Arkansas. Your mileage may vary.
+ TrackBacks (0) | Category: Aging and Lifespan | Biological News
Adam Feuerstein schools the Generex folks on what a "Treatment IND" really means, quoting chapter and verse from the FDA. The company's fans have made much of that designation for its flagship buccal insulin product. As has the company's CEO - but that link shows her making statements at investor conferences which are, on the face of them, in flat contradiction to the FDA's own understanding of such matters.
The article's worth reading even if you don't give two hoots about Generex, since it'll give you an understanding of what it means (and doesn't mean) when a company has a product designated for "compassionate use". It can also give you an understanding of what it means when a company misrepresents that status, but I think a lot of people here already know what that must mean. . .
+ TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | Regulatory Affairs
April 28, 2010
The Wall Street Journal has an article detailing some of Pfizer's plans in the biologics area: stepping in with second-generation versions of current winners from other companies. New versions of Rituxan and Enbrel are in the works, with the improvements mostly coming in how often the drugs need to be given.
They're not alone in this - Merck has announced that they're going to go after the same sorts of markets. And I can see the business rationale, since the original products have been such huge successes. But these new versions are going to be different enough that they're certainly not "biosimilars" or "biogenerics" - they're new substances, which will require their own complete safety/efficacy clinical workup. And by the time they get to market, some of these may be up against (or close to being up against) lower-cost versions of the original therapies, so the insurance companies are going to have to see some real benefit before they switch away.
So while some of these may well work out, not all of them will. It looks like a worthwhile thing to try, but it's not a sure road to riches. That's the thing about this industry these days - all those roads appear to be blocked off and plastered with "Detour" signs. . .
+ TrackBacks (0) | Category: "Me Too" Drugs | Drug Development | Drug Prices
I've had a few requests to make the blog available in a Kindle
version. So after a visit to the innards of Amazon, here it is, for those of you who'd like things delivered in that format. I don't own one of them myself, but I can definitely see the point of one (or something like it).
+ TrackBacks (0) | Category: Blog Housekeeping
Christoph Westphal gave what by all accounts was a very interesting talk at the recent Bio-IT conference. And considering his track record in company formation, he's well worth listening to. But concerning the recent controversy over the compounds and results from his most recent success (Sirtris), I found this part of his speech. . .well, interesting:
"There’s a debate in the academic world,” Westphal acknowledged. “We don’t know the specific molecular mechanism of why you need a specific substrate on the in vitro screen to find Sirt1 activators. Pfizer, Amgen, GSK, Sirtris, everyone in academia agrees on that. Then the question is: Is the mechanism direct on SIRT1 or indirect on SIRT1? Everyone in the field agrees our molecules have beneficial effects in animals, and I hope they will in man soon. The specifics of the mechanism are under debate. This kind of thing will be debated for ten years.”
Emphasis mine. And I emphasize that part because Pfizer specifically tested one of the highlighted Sirtris compounds, SRT1720, and was unable to reproduce the in vivo effects. So no, I wouldn't say that "everyone agrees" on this point. Not quite.
Westphal says that there's another paper in press that might be able to clear things up a bit, so we'll see what that one has to say. And he's right that the clinical results are what will really settle these questions - but we're going to have to wait a while for those. For now, agreement on a lot of key points remains hard to come by. . .
+ TrackBacks (0) | Category: Aging and Lifespan | Business and Markets
I wrote here some time ago about human cells actually making their own morphine - real morphine, the kind that everyone thought was only produced in poppy plants. Now there's a paper in PNAS where various deuterium-labeled precursors of morphine were dosed in rats, and in each case they converted it to the next step in the known biosynthesis. The yields were small, since each compound was metabolically degraded as well, but it appears that rats are capable of all steps of a morphine synthesis from at least the isoquinoline compound tetrahydropapaveroline (THP).
And that's pretty interesting, because it's also been established that rats have small THP in their brains and other tissues - as do humans. And humans, it appears, almost always have trace amounts of morphine in the urine - which leads one to think that our bodies may well, in fact, be making it themselves.
Why that's happening is quite another question, and where the THP comes from is another one. Working under the assumption that all this machinery is not just there for the heck of it, you also wonder if this system could be the source of one or more drug targets (I spoke about that possibility here). What you probably don't want to assume is that these targets would necessarily have to do with pain. We still don't know if there's room to work in here. But it's worth thinking about, if (for no other reason) to remind ourselves that there are plenty of things going on inside the human body that we don't understand at all.
+ TrackBacks (0) | Category: Biological News | The Central Nervous System
April 27, 2010
I've heard that Merck told employees today that the Union site (an old Schering-Plough facility) will be closed. Apparently employees from both the Rahway and Union sites will be part of a pool when it comes to job cuts as a result of this, though - it's not just everyone who was working at Union.
This doesn't surprise me, actually. Union was one of the oldest of the Schering-Plough sites (perhaps the oldest after the company moved out of Bloomfield in 1992?) It always seemed a bit odd to have it and Kenilworth right next to each other, and throwing Rahway into the mix meant that something was probably going to give. . .any more details from the Merck people out there?
+ TrackBacks (0) | Category: Business and Markets
Every year there's a big Cambridge Science Festival, which many companies and institutions around here get involved with. My own company is no exception, and we're holding a "Networking Event" for students in academia tomorrow afternoon. Flyers for it went out a while back to all sorts of institutions around the area, but for anyone who's also a reader of this blog, I wanted to mention that I'll be giving a 30 minute talk at this one. So if you're in the target audience, feel free to stop by (4 PM Wednesday, 200 Sidney Street). I believe that there was an RSVP by last Friday, but drop me an email if you missed it, because I don't think we're going to lock anyone out if you really want to come, either.
+ TrackBacks (0) | Category: Blog Housekeeping
I've said several times that I think that mass spectrometry is taking over the analytical world, and there's more evidence of that in Angewandte Chemie. A group at Justus Liebig University in Giessen has built what has to be the finest imaging mass spec I've ever seen. It's a MALDI-type machine, which means that a small laser beam does the work of zapping ions off the surface of the sample. But this one has better spatial resolution than anything reported so far, and they've hooked it up to a very nice mass spec system on the back end. The combination looks to me like something that could totally change the way people do histology.
For the non-specialist readers in the audience, mass spec is a tremendous workhorse of analytical chemistry. Basically, you use any of a whole range of techniques (lasers, beams of ions, electric charges, etc.) to blast individual molecules (or their broken parts!) down through a chamber and determine how heavy each one is. Because molecular weights are so precise, this lets you identify a lot of molecules by both their whole weights - their "molecular ions" - and by their various fragments. Imagine some sort of crazy disassembler machine that rips things - household electronic gear, for example - up into pieces and weighs every chunk, occasionally letting a whole untouched unit through. You'd see the readouts and say "Ah-hah! Big one! That was a plasma TV, nothing else is up in that weight range. . .let's see, that mix of parts coming off it means that it must have been a Phillips model so-and-so; they always break up like that, and this one has the heavier speakers on it." But mass spec isn't so wasteful, fortunately: it doesn't take much sample, since there are such gigantic numbers of molecules in anything large enough to see or weigh.
Take a look at this image. That's a section of a mouse pituitary gland - on the right is a standard toluidine-blue stain, and on the left is the same tissue slice as imaged (before staining) by the mass spec. The green and blue colors are two different mass peaks (826.5723 and 848.5566, respectively), which correspond to different types of phospholipid from the cell membranes. (For more on such profiling, see here). The red corresponds to a mass peak for the hormone vasopressin. Note that the difference in phospholipid peaks completely shows the difference between the two lobes of the gland (and also shows an unnamed zone of tissue around the posterior lobe, which you can barely pick up in the stained preparation). The vasopressin is right where it's supposed to be, in the center of the posterior lobe.
One of the most interesting things about this technique is that you don't have to know any biomarkers up front. The mass spec blasts away at each pixel's worth of data in the tissue sample and collects whatever pile of varied molecular-weight fragments that it can collect. Then the operator is free to choose ions that show useful contrasts and patterns (I can imagine software algorithms that would do the job for you - pick two parts of an image and have the machine search for whatever differentiates them). For instance, it's not at all clear (yet) why those two different phospholipid ions do such a good job at differentiating out the pituitary lobes - what particular phospholipids they correspond to, why the different tissues have this different profile, and so on. But they do, clearly, and you can use that to your advantage.
As this technique catches on, I expect to see large databases of mass-based "contrast settings" develop as histologists find particularly useful readouts. (Another nice feature is that one can go back to previously collected data and re-process for whatever interesting things are discovered later on). And each of these suggests a line of research all its own, to understand why the contrast exists in the first place.
The second image shows ductal carcinoma in situ. On the left is an optical image, and about all you can say is that the darker tissue is the carcinoma. The right-hand image is colored by green (mass of 529.3998) and red (mass of 896.6006), which correspond to healthy and cancerous tissue, respectively (and again, we don't know why, yet). But look closely and you can see that some of the dark tissue in the optical image doesn't actually appear to be cancer - and some of dark spots in the lighter tissue are indeed small red cells of trouble. We may be able to use this technology to diagnose cancer subtypes more accurately than ever before - the next step will be to try this on a number of samples from different patients to see how much these markers vary. I also wonder if it's possible to go back to stored tissue samples and try to correlate mass-based markers with the known clinical outcomes and sensitivities to various therapies.
I'd also be interested in knowing if this technique is sensitive enough to find small-molecule drugs after dosing. Could we end up doing pharmacokinetic measurements on a histology-slide scale? Ex vivo, could we possibly see uptake of our compounds once they're applied to a layer of cells in tissue culture? Oh, mass spec imaging has always been a favorite of mine, and seeing this level of resolution just brings on dozens of potential ideas. I've always had a fondness for label-free detection techniques, and for methods that don't require you to know too much about the system before being able to collect useful data. We'll be hearing a lot more about this, for sure.
Update: I should note that drug imaging has certainly been accomplished through mass spec, although it's often been quite the pain in the rear. It's clearly a technology that's coming on, though.
+ TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Drug Assays
April 26, 2010
Last year I wrote about the hideous structure of maitotoxin, with a note about how various groups were kicking around synthetic approaches to it. Now K. C. Nicolaou has a paper out in JACS on the synthesis of a portion of the molecule, which includes the line: ". . .as a prelude to a possible synthesis of large domains of this molecule for biological investigations. . .". Yeah, sure. Betting will now commence on whether or not he'll be able to resist going for the whole thing. As to whether or not that's a good idea, well. . .my views on the subject have already been aired pretty thoroughly.
+ TrackBacks (0) | Category: Chemical News
I don't think we saw this one coming: Charles River Labs has announced that they're buying WuXi PharmaTech. They're paying about a 28% premium over Friday's closing stock price - Charles River's CEO will stay on, and WuXi's founder (Li Ge) will serve as executive VP under him.
Charles River, which is strong in the animal-testing end of the business, has apparently decided that Wu Xi is one of their biggest competitors (I'd agree) and has decided to try to stake out a leading position in the whole contract-research space. It's interesting to me that the folks at Wu Xi bought into this reasoning as well, although (since they're a publicly traded company here in the US), a lucrative stock offer can be its own argument. One now wonders, though, about the company's statements on re-staffing some of their US labs when economic conditions improve. . .
+ TrackBacks (0) | Category: Animal Testing | Business and Markets | Drug Assays | Drug Development
Well, the first thing I can tell everyone is that I think the entire editorial staff at Chemical and Engineering News read every comment to this post. And that includes the nasty ones, for sure. The readership around here is a self-selected lot, and the commentors even more so, but the quick volume of responses got a lot of attention.
I noticed a lot of discussion around the "Do we really need more chemists?" theme. Readers will be interested to know that many people at the magazine share their uneasiness with some of the never-ending "scientist shortage" talk. The ACS's own figures (which many here seem to feel are too low) nevertheless show the highest unemployment rates among chemists they've ever shown.
Outside of the issues that came up here on the site, one of the things I suggested was more focus on smaller companies - both in terms of plain science/business news, but also with reference to where they come from. My point was that chemists reading C&E News see all sorts of items about various companies, but it's as if they've condensed out of the air. If there really is any sort of economic recovery coming on, I think that one of the best chances to lower our profession's jobless rate is through startup formation, and I told the people at the magazine that they should keep this in mind.
I wasn't in the discussion groups that touched on another theme that came up here in the comments, the long-running "Women in Chemistry" articles. And it's probably a good thing - I tend to be pretty much an eye-roller when it comes to corporate diversity programs, but I get the feeling that no one at the ACS (or its publications) feels safe doing so much as that, even if they were so inclined. For the record, I have no problem at all, of course, with women in chemistry, or anyone else in chemistry - it's just the let's-all-join-hands march-of-progress stuff that can get tedious. The people whose march through the ranks I most want to promote are the people who are good at it, whoever that might turn out to be.
One thing I found interesting is that the writers, although almost all of them have chemistry training, seem to feel apart from the actual business of chemistry. That's understandable, I suppose, because their profession is really journalism. I told them that not being a journalist made writing a blog a lot easier. . .
+ TrackBacks (0) | Category: Chemical News | Current Events
April 21, 2010