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: firstname.lastname@example.org
August 30, 2006
If you want to make your friends in the cell culture lab jump, just walk up behind them and shout "mycoplasma!" (What's that? You say you have no friends in the cell culture lab? Hmm. . .)
Mycoplasma is a scary word because they're scary little organisms. They're bacteria, just barely, running much smaller than usual and without any sort of cell wall. They also have the tiniest genomes you're likely to ever see - being parasitic allows them to get away with a pretty limited instruction set. They can cause diseases in humans and other animals (excellent review here), but they just love to hang out with your cultured cell lines, too.
From their (admittedly rather limited) perspective, what's not to like? Constant temperature, lots of food, and plenty of well-taken-care-of cells to mooch off of. Problem is, once they get in there, they alter the behavior of the cells they've infected, and you can't trust the results of your assays with them any more. Every cell culture lab tests for these things, and every one of them still has the occasional outbreak. It's the price of doing business. If the cells aren't precious, they're tossed - if they are, there are some antibiotics that will generally kill the little creatures off, but you still have to watch things closely for a while. (If you don't want to test them yourself, you can send samples to these guys, and they'll do it for you).
There have been periodic mycoplasma spasms in many research areas, as various groups have found that their results are suspect due to contamination. Since the little beasts pass right through filters that will strain out normal bacteria, and can't even be reliably seen under normal microscopy conditions in many cell cultures, a little paranoia is justified. Have you checked your cells recently?
+ TrackBacks (0) | Category: Drug Assays
August 29, 2006
There was a comment on the "Airplanes and Chemicals" post that brought up something I've been meaning to address. Says Steve, after describing an old TV show that gave rather too detailed a picture of nitroglycerin synthesis:
While I am first in line to defend freedom of speech and would balk at anyone trying to muzzle a scientist, I think as scientists we all have a personal and professional responsibility not to place metaphorical loaded guns into the hands of children, much less of certifiably crazy adults.
Exactly. I said something of the sort in the post itself, and I wanted to reiterate it. As a working organic chemist, I can yammer on for quite a while about explosive reagents, and while I've never (fortunately) had any need to make any of the classic explosives themselves, I know a fair amount about their synthesis and purification just through reading and general lab experience. But I'm not going to talk about them.
Now, I realize that over there on the right I have a whole category of alarming lab stories and another one of horrible reagents. But the first set of stories mostly concern common reagents and procedures made dangerous by the presence of fools, and won't be much help to someone actively seeking to do harm. And as for the second set, I've deliberately avoided some topics. I won't work with acetone peroxides, that's for sure, but I won't do a detailed blog post on them, either.
And this brings up another issue. Years ago, my wife had a somewhat paranoid co-worker who thought that his experiments were being sabotaged by someone else in the lab. That wasn't the case, but we got to talking about how easy it would be, if one were so minded, to completely screw up the work of a research lab. There are all sorts of ways to do it in an immediately noticeable fashion, but there are many that would be much harder to track down.
For a biologist, going in and switching the labels around on the cell cultures in the freezer would be a start. A little toxic additive or two in the growth media would slow things down, too, as would a few pellets of sodium hydroxide in various buffer solutions. For chemists, messing with the TFA that's used as an additive in the HPLC solvents would have everyone chasing their tails for a while, as would substituting the palladium catalysts with similarly colored iron or chromium compounds. Some methanol in the ethyl acetate bottle, to mess up all the TLCs? A little sulfur in the hydrogenation catalysts? Once you start thinking of these things, the ideas just tumble out.
It's the same with larger and more terrible issues. I, like (I'm sure) many other organic chemists, could sit down and think up all kinds of nasty stuff if I were so minded. I'm not, fortunately, but if I ever found myself on the rough end of a guerrilla war, I might be useful to have around. (Science fiction fans may recall a scientist character improvising chemical weapons in such a situation in Niven and Pournelle's potboiler disaster novel Lucifer's Hammer). The chemical weapons of World War I seem to have been an example of just this sort of thing, with university chemists basically clearing the shelves of all sorts of nasty lab reagents to toss them experimentally at the enemy.
No, it's easy, although weirdly depressing, to come up with interesting horrible ideas. (I'm reminded of how C. S. Lewis said he wrote from a demon's point of view in The Screwtape Letters). But it's not something I sit around doing, and I'm not going to share any of those thoughts I might have already. The world has enough horrible ideas as it stands.
+ TrackBacks (0) | Category: Chem/Bio Warfare
August 28, 2006
Today while walking through the library I passed the shelves where the Chemical Abstracts indices still sit. They don't appear to have been touched in some time - I certainly haven't disturbed them.
CA is the repository for abstracts of almost all the papers that bear on chemistry throughout the world's scientific literature, and for data on all the chemical compounds that are described in them. It's one of the largest compendia of reference data in the world, as you'd expect. For many years, it was available only as a print edition, because, well, everything was available only in a print edition.
Every five years a collective index would be issued, to great rejoicing. These included indices by author, by chemical formula, by compound name, and so on. I remember when the 10th index came out, which covered the 1977-1981 literature, so I guess I go back to the 9th edition, although I'd never had much need (or ability) to use it while it was current. The coverage of the 10th index, though, ran from a year when I knew little or no chemistry to a time when I'd finished my sophomore organic course and had some idea of what the papers it referenced were talking about.
The 11th came out while I was in graduate school, and man, was I glad to see it. The 10th had become rather ancient in the meantime, and my need for access to the literature had reached unheard-of levels as I wrestled with my PhD. Digging through the more recent volume-by-volume indices to catch up had become quite painful. But it in its turn began to show its age. The 12th collective index showed up after I'd been in industry for three years or so, and I was glad to see it as well. We had a library staff that would look things up for you, but I still found them no substitute for going down and digging around firsthand. I gave that edition a good workout, and I remember being quite distressed when the rows of softcover volumes disappeared for a while for binding.
But things changed. The 13th index, from 1992 to 1996, is the last one whose physical covers I ever opened, and I think that was only once or twice. The library here never even bothered to get it hardbound, and the big softcover volumes are slumped against each other on their shelves. I have never even seen a copy of the 14th index, and I wonder how many copies of next year's 15th will even be printed. Whether there will even be a hard-copy version of the 16th in 2012 is anyone's guess, but I'd be willing to bet against it.
What happened, naturally, was the machine that you're using to read this blog. Even while I was in graduate school, you could access Chemical Abstracts via a command-line interface through one of those rockin' 1200 baud modems, and I was the person in our research group designated as the high priest. There was one terminal in the library hooked up, with a special key to open the door. I still have copies of the manual pages somewhere in my files. I'm kind of surprised that I don't have the key as well, but they must have made sure that it was turned in.
The first time I used CAS Online, I felt as if I'd been given magical powers. Wildcards! Variable atoms and chain lengths! I talked everyone's ears off about the kind of searching that could be done, and as I recall, the big issue was convincing people that the online method differed not only in degree, but in kind. You could, of course, do things that were completely impossible to do with the print edition, a fact that is mostly appreciated now by people who are at least 40 years old. That is, people who have done it the old way. Fewer and fewer do, and good riddance to it.
If you'd parted the curtain of Time and shown me 2006 literature searching on a 2006 computer, I'd probably have fainted. Similarly, if you'd told me back in 1985 that I never would see the 14th CA Collective Index or any past it, I probably would have taken it as a prophecy of nuclear war. Something better happened instead.
+ TrackBacks (0) | Category: The Scientific Literature
August 27, 2006
After my article on the role of carbon isotope testing in the Floyd Landis case, a question has come up several times in the comments and in my e-mail: since it's well-known that Landis was taking cortisone for his hip, could this have skewed the isotope ratios in his testosterone?
I doubt it very much, and here's why: first off, around 95% of the circulating testosterone in the male body is produced in the testes. For Landis's isotope ratios to be off a significant amount through something involving his own metabolic pathways, this is the only place that's worth looking.Testosterone and the other steroids are produced from cholesterol. The testes and other steroidogenic tissues have a stockpile of cholesteryl esters ready to be used for steroid synthesis, so it's going to be an uphill fight to alter things by any route, given that reserve.
Now it's time to dive into some biochemistry for the next few paragraphs - follow along if you like, or jump down to near the end if you don't want to see a lot of structures. OK, in steroid synthesis the first thing that happens is the chewing off of a side chain on the D ring to form pregnenolone, which is then turned into progesterone. That's the starting material for both testosterone and cortisol/cortisone. (Note that those last two are interconverted in the body by the 11-HSD enzymes).
Going down these different pathways, testosterone and cortisol end up with rather different structures. Cortisol's more complex. If you flip back and forth between those links in the previous paragraph, you'll see that the A and B rings are the same in both, but the C ring of cortisol has an extra hydroxyl group at C11, and it also has some oxidized side chain left at C17, which has been completely chopped off in testosterone. The question is, can you get from cortisol back to something that could be used to make testosterone?
I can believe the side-chain transformation much easier than the C-11 deoxygenation. Here's the metabolic fate of cortisol. Note that all these metabolites still have an oxidized C-11 - if anything is going to be recycled into testosterone, that C-11 is going to have to be reduced back down. And if there's a metabolic pathway that does that to any degree, I can't seem to find out anything about it. If it's a feasible pathway at all, it must be very minor indeed. If any steroid experts can shed light on this, I'd be glad to hear the details. (There's also the question of how long such intermediates would be available, versus their half-life before further metabolism and excretion, but that's a whole other issue).
No, if Landis's carbon isotope ratios are off significantly - and we haven't seen the official numbers yet - then it's hard for me to see how the cortisone injections could have much to do with it. We'll be stuck, in that case, with either conspiracy theories or with the conclusion that Landis used testosterone, and if it comes to that, I know which one I'm most likely to believe.
+ TrackBacks (0) | Category: Analytical Chemistry | Current Events
August 24, 2006
Turns out that I had another patent issued the other day. The way I usually find out about these things isn't through a note from the US Patent and Trademark Office - they have enough to do already. And it's not via a note from my company, although they do eventually mark the event in a way that's dear to my heart and which shows up in my paycheck. No, the quickest notification is via junk mail from the patent plaque companies.
If you're not in an industry that does a lot of patenting, you might not have run across these people. What they do is offer (for a price, naturally) a wall plaque to show off your patent. These come in all sorts of designs and combinations - just Google the phrase "patent plaques" and you'll get all the options you could ever need. It's a competitive business, and the real go-getters use the latest updates to the patent databases as their mailing lists.
What I find interesting is the language that the brochures use. They seem aimed at people with self-esteem issues. The words "respect" and "recognition" occur frequently, as do "accomplishment" and "achievement". Einstein and Edison come up more often than they do in normal conversation. The more expensive options (better-looking wood, more three-dimensional etching in the metal, what have you) are pitched to some hypothetical audience of demanding achievers who would clearly settle for nothing less. The general tone of the copy is similar to the ads you find in airline in-flight magazines, set relentlessly to a level that's designed to flatter the intended audience and play to their fantasies.
Many of the pitches thus seem to be aimed at individual inventors who have been issued their first patent and want to let everyone know about it. I'm sure that's a big part of the market, and the rest of it is probably taken up by large companies who get a discount on their orders for their employees. I have a stack of the things myself, given to me by the companies I've worked for. I don't mind having them, but they're not on my wall, and I'd never order one on my own - not least because you can't get anything out of these outfits for less than about $70 for the El Cheapo Maximo model. The Deluxe Edisonian Hyperventilator plaques can go up past $300, by which time you're looking at rich Corinthian leather and who knows what else. I await the future LCD-screen option that displays a moving model of the invention.
+ TrackBacks (0) | Category: Patents and IP
August 22, 2006
Via the excellent Arts and Letters Daily, I found this piece by science writer K. C. Cole on dealing with editors in the popular press. She and others in her field have had their difficulties over the years when writing about things that even the researchers involved are confused about:
Editors, however, seem to absorb difficulty differently. If they don't understand something, they often think it can't be right - or that it's not worth writing about. Either the writers aren't being clear (which, of course, may be the case), or the scientists don't know what they're talking about (in some cases, a given).
Why the difference? My theory is that editors of newspapers and other major periodicals are not just ordinary folk. They tend to be very accomplished people. They're used to being the smartest guys in the room. So science makes them squirm. And because they can't bear to feel dumb, science coverage suffers.
She points out some of the problems - that many scientific discoveries deal with things that are more or less invisible to the ordinary senses, happen on time scales that are too short or too long to be easily perceived, contradict some common-sense notions of what must be right, and so on.
There's also the problem that, as she correctly observes, that sometimes there is no description in lay language that can really explain a topic. My guess is that pure mathematics suffers from this the most: try explaining the Reimann zeta function in one coherent paragraph to someone who doesn't know much math. Following right on math's heels, as usual, is physics, but its weirder aspects can have a gee-whiz factor that makes up for their difficulty. Meanwhile, the fields I spend my time in (chemistry and biology) have their incomprehensible moments, but I think that they're amenable to explanation most of the time.
Which brings up a challenge. I've been trying to think of the most difficult thing to explain in chemistry to people who don't know the field. Since I have readers in both camps, I'll invite the pros to suggest some tough topics, and I'll tackle, in reasonably de-geeked language for the general readership, whichever one gets the most votes. The chemists can then comment on how accurate the explanation really was and suggest modifications, and we'll end up with something that might be useful. If this idea proves popular, we'll run one every so often and put it in a new category page.
I may come out of this looking like an idiot, but being willing to run that risk is an important part of my research style. Let's see how it works in the blogging business. Topics, anyone? I'd suggest something with a good mix of usefulness and broad interest along with general public incomprehension (NMR might be a good example).
+ TrackBacks (0) | Category: General Scientific News
August 15, 2006
I've taken a few good swings at Kevin Trudeau around here, naturally enough, since he's going around telling everyone that my industry is poisoning them. I get some Google traffic from people searching for information about him, which makes me happy, since what they read here might possibly prevent them from giving this sleazy scam artist their money.
But I've noticed some odd search phrases turning up, things like "How old is Kevin Trudeau" and "Kevin Trudeau real age". Some looking around confirmed my fears. Yes, it seems that Trudeau is going around telling people that he only looks like he's in his forties - when, according to him, he's actually seventy years old. This statement seems to be confined to his personal appearances, because it's hard to track down in print. But it's out there. And it's a lie, as numerous legal records (such as his convictions for credit card fraud) will verify. This shows a combination of greed and contempt for his own audience that you don't come across very often. I'd want to get my clothes dry-cleaned if I brushed up against him by mistake, but you have to admit, he's quite a specimen.
So, for anyone who comes across this page by a Google search, here's the short answer: Kevin Trudeau is not seventy years old. This is an outrageous lie, being told to your face by an equally outrageous excuse for a human being. Trudeau is telling you this whopper for one reason: because he wants your money. Don't give it to him. Too many people have already.
Meanwhile, the marketing practices I spoke about last year continue - he's still slamming phone customers for his book with unwanted subscriptions to his $71 newsletter, for example. Here's one of the many folks who've found that getting Kevin Trudeau's hands off your credit card is next to impossible - and here's another. That applies to the poor suckers who pay $100 each to see him live, too - refunds are mighty slow in coming. And it appears that at least one of his front companies, Media Planet, has officially "gone out of business" in an effort to strand as many people as possible.
Naturally, he has another book out. And naturally, it's accompanied by a mudslide of lies and arrogant nonsense, such as the repeated claims that the FTC "censored" his first book, and that this one has all the good stuff in it that was cut out. (His real interactions with the FTC are considerably more complicated). This is merely a ploy to extract more money from his audience, even the ones who felt ripped off when they paid for his first book only to find it virtually content-free. This one is, naturally, full of the same vacuous gibberish as the first one. Naturally, it's $29.95.
Reputable publishers, though, are looking at the stacks of money that Trudeau is hauling away and wondering how to get some of that health-conspiracy mongering action. And what is this benefactor of humanity doing with some of the cash? Why, bankrolling a professional pool tournament. Where? Las Vegas. Naturally.
+ TrackBacks (0) | Category: Snake Oil
I'm going to be doing some traveling for the next few days, so posting will be intermittent, depending on time and internet access. E-mail, similarly, will stack up until the middle of next week - anyone with lucrative publishing offers, please wait until then to send 'em to the top of the queue. I think the drug industry will manage just fine without me. . .
+ TrackBacks (0) | Category: Blog Housekeeping
August 14, 2006
The New England Journal of Medicine has published an authoritative wrap-up of the Tegenero/TGN1412 case. This, you'll remember, was the T-cell stimulating antibody trial that went disastrously wrong, sending six first-in-man voluteers into intensive care. (They remained there for one to three weeks, but all of them survived). As minor side effects, this event also sent the company into bankruptcy and the drug candidate straight down the waste chute.
The article makes for grim reading, and I'd be interested to hear what some of the med-bloggers have to say about it. I'm no MD, but the patient charts on admission to the ICU look pretty terrifying to me - pulmonary and renal failure, coagulation throughout the vasculature, severe (and surprising) near-total loss of lymphocytes and monocytes, and much, much more. The phrase "empirical treatment" shows up a lot in the account of their cases, which I take to mean "what seemed reasonable, since we'd never seen anything quite like this before".
As it turned out, the empirical treatment - intubation, dialysis, transfusions, whacking doses of steroids and anti-IL-2 receptor antibodies - seems to have done the trick. This was a "cytokine storm", a known immune phenomenon never observed in such isolation before. (It's usually set off by infection or some endotoxin).
An accompanying perspective article talks about some the issues that were tossed around on this site at the time (a href="http://pipeline.corante.com/archives/clinical_trials/">here - scroll back to March), such as the similarities (and differences) between the CD28-targeting Tegenaro antibody and the comparatively successful ones targeting CLT-4. No one is still quite sure why TGN1412 did what it did, but the authors have a couple of suggestions: for one thing, the affinity of the antibody was probably quite different in humans than in the other species used preclinically. In primate studies, the animal were dosed with the exact same antibody (anti-human-CD28) used in the clinical trial, but it surely has weaker binding to the primate T-cell receptor.
Another factor, which as they point out is not often appreciated, is that laboratory animals (particularly rodents) have much more naïve immune systems than wild-type animals (like us). The clinical trial subjects surely had far more memory T cells, activated by previous exposures to all sorts of antigens, than the mice used in the early models. Perhaps this added to the trouble.
At any rate, we don't seem to be hearing much about how TGN1412 might still go back into the clinic, like we were at the time. The NEJM authors correctly point out that before anyone goes after any of the costimulatory T-cell receptors again, we're going to need to know a lot more than we do now. And even then, you have to think, it's going to require an awful lot of nerve.
+ TrackBacks (0) | Category: Clinical Trials
August 13, 2006
OK, some of this is going to sound like Sanskrit to my non-chemistry readership, but here goes:
1. When's the last time you held a paper copy of JACS in your hand? For me, I think it's been at least two years. They could be running swimsuit covers now and I wouldn't know about it.
2. Are ionic liquids actually good for anything, other than publishing papers about them?
3. To combine those first two, if you wrote up a paper about a ring-closing metathesis reaction to make a nanoscale structure in an ionic liquid, would the journals even bother sending it to a referee before immediately publishing it?
4. Are they ever going to hand out a chemistry Nobel for palladium coupling reactions? Or have the Swedes decided that credit is too tangled? (Not to mention the fact that not all the key early players are still alive). But if ring-closing metathesis deserves one (and I have no problem), doesn't the Suzuki reaction?
5. Weren't they promising us benchtop NMR machines back about twenty years ago? Does anyone expect to ever see the hypothetical personal benchtop LC/MS machine? Maybe we'll have them in our flying cars.
6. Will Chemical and Engineering News ever go a year without running a headline that says "Salaries for Chemical Engineers Still Higher". As far as I can tell, they haven't missed since about 1982.
+ TrackBacks (0) | Category: Chemical News
August 10, 2006
I've been remiss in not covering the Plavix situation, which is quite a story. The huge-selling anticoagulant is marketed in the US by Bristol-Meyers Squibb and in the rest of the world by Sanofi-Aventis. It's been the target of the Canadian generic firm Apotex, who've maintained that key parts of its patent coverage are invalid. They won the right from the FDA back in January to sell their generic form - but keep in mind that the FDA is not concerned with patent law, only the drug's manufacturing standards and identity with the original version.
The company was in the middle of their patent suit with BMS and S-A, and were holding back to see how that would go. In March, though, a deal was cut: Apotex agreed to wait until 2011, the lifetime of the (unchallenged) patent, and in return they got paid by the larger firms and received a guarantee that they wouldn't be undercut until then.
Paying generic firms to go away is not unheard of, but companies can put themselves at risk when such deals are made too blatantly. This one fell apart, big-time, last month. Not only was it rejected by various state attorneys-general, but a criminal investigation was launched into the whole matter.
The ceiling tiles really began to rain down at that point. There was a clause in the agreement that if the deal didn't go through, Apotex could start selling its generic version with five days notice, and that's exactly what they've started doing as of earlier this week. The generic isn't all that much cheaper, but it's enough to torpedo the branded version.
What's more, it appears that BMS and Sanofi-Aventis limited their potential recourse. Under the usual rules, they'd be able to sue and obtain triple damages if they won, but they seem to have waived that right, along with several others. This would seem to be an indicator of just how much they wanted to keep the generic off the market, and how hard a bargain Apotex drove. It's enough to make you wonder if Apotex factored in, up front, the chance of the whole thing being rejected and decided to give their rivals enough rope with which to hang themselves.
Update: as pointed out in the comments, the CEO of Apotex is making it sound like that was exactly the plan. Perhaps he's laying it on a bit thick, but he's in a position to, isn't he?
Shares of both Bristol-Meyers Squibb and Sanofi-Aventis took a fine hammering, as you can well imagine, since Plavix represents about 30% of BMS's profits. (Here's a read-'em-and-weep chart). Apotex is privately held, which is a shame in a way, because it would have been something to see what the trading in their stock would have been like. Sanofi may try to obtain an injunction to stop the generic sales, but no one seems to think that it will be granted - partly because of all those Apotex-favoring terms that the companies agreed to originally.
It's difficult to see how this could have worked out more horribly for the two big companies here: their best-selling drug is under attack five years early, they've signed away their rights to do much about it, the analysts are downgrading their stock and the financial rating agencies are looking at lowering their credit ratings, and the criminal investigation is rolling right along. Short of a meteor strike or a plague of frogs, I'm not sure what else could go wrong. And the worst part is, they brought it on themselves. Their patent position should have been stronger in the first place to protect a compound of this importance, and they shouldn't have pushed the envelope so much with their go-away payments to Apotex. It didn't have to be this way. Did it?
+ TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Patents and IP | The Dark Side
I've already been asked about today's news of a plot to bring chemical explosives on to commercial flights in Britain. Naturally, like most other chemists, I have opinions and speculations about how people might do this, but I'm going to keep them to myself. I've no desire to be used as reference material for such things, unlikely though that might be. If there are later disclosures (unlikely) about the compounds and methods used, I may comment on them then, but I'm not going to add to the available information about homemade explosives for terrorism.
And in the spirit of honi soit qui mal y pense, it is my sincere wish that anyone who investigates such things blow themselves up very early in their R&D program.
+ TrackBacks (0) | Category: Current Events
August 9, 2006
Ray Kurzweil's people sent me a copy of his book The Singularity is Near quite a while ago when it first came out. I kept meaning to write about it, but several things kept interfering. One of the things was the book itself.
I'm of two minds about Kurzweil and the worldview he represents. As many will know, he's about as much of a technological optimist as it's possible to be, and I have a lot of that outlook myself. But I wonder - does it extend to my own field of research? More generally, and more disturbingly, am I only optimistic about the areas whose details I don't know very well?
These questions came up again when I read a recent op-ed by Kurzweil in the Philadelphia Inquirer. It's a good summary of his thinking, and it includes this paragraph:
"The new paradigm is to understand and reprogram our biology. The completion of the human genome (our genetic code) project three years ago is now allowing us to do that. This process is also exponential: The amount of genetic data we are able to sequence (decode) has doubled every 10 months, while the price for decoding each gene base pair drops by half in the same time frame (from $10 per base pair in 1990 to less than a penny today). For example, it took us 15 years to sequence HIV, yet we sequenced the SARS virus in only 31 days, and can now sequence a virus in just a few days."
That, to me, is a mixture of accurate information, reasonable optimism . . .and unreasonable assertions. Yes, we're sequencing things faster than ever before, and part of that increase comes through computational advances, which are a ferocious driver of everything they concern. But it's a very long leap from that to saying that such sequencing is allowing us to "reprogram our biology". Reading the DNA letters quickly does not, unfortunately, grant us an equally speedy understanding of what they mean. And we shouldn't forget that sequences are only a part of biological understanding, a realization that the genomics boom of the late 1990s drove home very forcefully and expensively.
Then we come to this:
"Being able to decode the human genome allows us to develop detailed models of how major diseases, such as heart disease and cancer, progress, and gives us the tools to reprogram those processes away from disease. For example, a technique called RNA interference allows us to turn unhealthy genes off. New forms of gene therapy are also allowing us to add healthy new genes. And we can turn on and off enzymes, the workhorses of biology. Pfizer Inc.'s cholesterol-lowering drug Torcetrapib, for example, turns off one specific enzyme that allows atherosclerosis, the cause of almost all heart attacks, to progress. Phase II FDA trials showed it was effective in preventing heart disease, so Pfizer is spending a record $1 billion on the phase III trials. And that's just one example of thousands of this "rational drug design" approach now under way."
Oh, dear. Let's take these in order. First, being able to decode the human genome does not allow us to develop detailed models of how major diseases progress. It allows us to begin to think about doing that, and to be, for the most part, mistaken again and again. Many diseases have a genetic component, or two, or a thousand, but we don't understand them yet, nor their incredibly tangled relationships with development and environment. You'd think we'd know the genetic components of diabetes or schizophrenia, but we don't, and it's not for lack of trying. And as for the diseases for which the genetic component is less important, the sequencing of the human genome has been a non-event.
And yes, there is a highly interesting technique called RNA interference which can turn "unhealthy genes" off. It works quite well (although not invariably) in a glass tube or a plastic dish. A plastic dish, that is, in which you have carefully cultered cells in which you have carefully determined the presence of the gene of interest. And for many interesting conditions, you first need to find your gene, for which see above. Moving out of the cell culture labs, it should be noted that RNAi has significant hurdles to overcome before it can do anything in human beings at all, and may (like its forerunner, antisense DNA) still be destroying venture capital twenty years from now. Readers of this site once voted it the currently hyped technology most likely to prove embarrassing.
As for new forms of gene therapy allowing us to add healthy new genes, well, that's another hope that I'd like to see fulfilled. But there have been a number of disturbing and fatal complications along the way, from which the whole gene therapy field is still trying to recover. For Kurzweil to leave that sentence in the present tense, in the sense of this-is-happening-right-now, is putting it rather hopefully.
And yes, we can turn off enzymes. Some of them. This has nothing to do with gene sequencing or RNA interference, though, or any other particularly new technologies - enzymes as drug targets go back decades, and enzyme inhibitors as drugs go back centuries. Of course, you need to find your enzyme and make sure that it's relevant to the disease, and find a compound that inhibits it without inhibiting fourteen dozen other things, but that's how I earn my living.
And yes, Pfizer hopes to make all kinds of money off torcetrapib, but I'm not aware that they used a "rational drug design" strategy. In the industry, we tend to use that term, when we can use it with straight faces, to mean drug design that's strongly influenced by X-ray crystal structures and computational modeling, but I don't think that this was the case for torcetrapib. Kurzweil seems to be using the phrase to mean "drugs targeted against a specific protein", but that's been the dominant industry mode since the days of bell-bottoms. And if there are thousands of programs comparable in size torcetrapib, they must be taking place on other planets, because there's not enough drug development money here on Earth for them.
Finally, the end of the paragraph. Where does all this lead? Later in Kurzweil's article, he says:
"So what does the future hold? By 2019, we will largely overcome the major diseases that kill 95 percent of us in the developed world, and we will be dramatically slowing and reversing the dozen or so processes that underlie aging."
And here, I think, is where I can clearly differentiate my thinking from his. As opposed to a pessimist's viewpoint, I agree that we can overcome the major diseases. I really do expect to put cancer, heart disease, the major infections, and the degenerative disorders in their place. But do I expect to do it by 20-flipping-19? No. I do not. I should not like to be forced to put a date on when I think we'll have taken care of the diseases that are responsible for 95% of the mortality in the industrialized world. But I am willing to bet against it happening by 2019, and I will seriously entertain offers from anyone willing to take the other side of that bet.
Why am I so gloomily confident? For us to have largely overcome those conditions by 2019, odds are excellent that these new therapies will have to have been discovered no later than 2014 or so, just to have a chance of being sure that they work. That gives us seven years. It isn't going to happen.
So I'm back to wondering: am I a technological optimist at all? I must be, because I still think that science is the way out of many of our problems. But am I only optimistic about things of which I'm ignorant? That's probably part of my problem, yes, painful though it is to admit. Am I willing to be as optimistic as Ray Kurzweil? Not at all. . .
+ TrackBacks (0) | Category: Drug Development | General Scientific News
August 8, 2006
How time zips along - it's time already for the next trial addressing the scope and validity of Ariad Pharmaceutical's massive patent on NF-kB pathways. It's a bench trial this time (no jury), which I think could make a big difference. I wrote about this back in the spring - scroll down to April 11 and work your way up. You'll see me short 1000 shares of Ariad stock right before the first trial's jury verdict, which to my surprise went Ariad's way.
Another recent review of the situation can be found at CNN. It's a pretty good summary, although the first version they posted was somewhat bungled. I persist in my view that Ariad's patent is too broad and never should have been issued in its current form, and that the idea that Lilly should have to pay damages to them sets an awful precedent.
So how's Ariad stock been doing? Well, that short position has been working out just fine, as the chart since their trial win will make clear. The stock dropped fairly hard today, on no particular news that anyone seems to know about, other than the unsurprising fact that the company is still burning money at a good clip. I have no updates from the trial at all, unfortunately, so I don't know how it's been going, nor when it's expected to end. (Anyone with more information is more than welcome to comment!)
If time is weighing on you while you wait for a verdict, take a look at the Ariad message board on Yahoo, and meditate on just what function these things are supposed to serve. Almost no one there seems to have a clue about the stock, other than they really like it or really hate it. The inhabitants spend their time shouting either words of encouragement or random curses at each other; hardly any information is ever exchanged. The history of the messages posted there since Ariad's court victory make for a study in mass delusion, as people continue to assure themselves and whoever might be listening that the stock really has bottomed out and that there's nowhere to go but up, etc., all the time losing money almost every trading day. It's a wasteland even by the rigorous standards of Yahoo stock message boards.
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August 7, 2006
I wrote here on the appetite hormone ghrelin, the target of much research over the last few years. The short background on it is that it's important in feeding behavior, growth hormone secretion, brain development, and probably several other things we haven't stumbled on yet. Drug companies have taken notice, synthesizing ligands for the ghrelin receptor in hopes of finding a new therapy for obesity (and in hopes that its other activities won't lead to unacceptable toxicity).
Now a team from Scripps reports in PNAS on a rather forceful approach: vaccination. They developed several candidate vaccines to induce an immune response against various regions of the ghrelin peptide, and tried them out on rats. The most effective ones caused the rats to gain much less weight than their non-immunized control partners, despite chowing on just as many calories. Consistent with what's known about ghrelin's actions, the change in weight was almost entirely achieved through smaller fat deposits - lean body mass was spared. The group is still working on figuring out what happens to the extra calories, but some ghrelin experiments have shown that animals become more active and have higher resting metabolic rates when its signaling is blocked.
The effects correlated well with the circulating antibody titers, which argues well for a real immune effect, and there were no signs of a general off-target inflammatory response. That's important, because messing with the immune system, as I like to say, is like the medieval attempts to summon demons from Hell. Unfortunately, black magicians had at least a vague idea of how they'd send back down whatever they called up, but calling off the immune system is another thing entirely. Once activated, it doesn't stand down easily. We're a long way from trying this out in humans, particularly given some of the recent troubles with cutting-edge immunulogical ideas.
Still, these results are quite interesting and exciting. But they're also confusing, though, and don't those three always seem to travel together. The odd thing is that experiments had already been done by other workers who infused anti-ghrelin antibodies into directly into the brains of test rats, who rather dramatically stopped eating. Those results were one of the things that got the drug companies excited, in fact. The present authors advance several possible reasons for the difference between their results and the earlier ones - perhaps ghrelin has a direct effect on feeding inside the brain compartment, but not out in the periphery, for one. Or perhaps the immunization in these experiments didn't have much effect inside the central nervous system, which is immunologically rather separate from the rest of the body. Another possibility is that some other feeding mechanism kicked in to compensate for any appetite decrease that might have otherwise been seen. These are just some of the possibilities; the paper has half a dozen more.
What's clear is that ghrelin signaling is powerful stuff, and that altering is might lead to just the sort of phenotype that many potential customers dream about: eat the same amount of food, but don't put on any fat. But it's also clear that ghrelin signaling is very poorly understood, and any number of things could come along to change the story completely. No, there are a lot of questions to be answered before people start lining up to be vaccinated against getting fat. But just the thought of it is going to have the headline writers cheering.
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August 6, 2006
I've been re-reading the late Francis Crick's "What Mad Pursuit", as I do every so often, and something stuck me about his career. Crick came out of nowhere. He was a disgruntled physicist with no particular training in biology, and as far as I can tell, no one (outside of a small circle of co-workers) had ever heard of him while he did the work that won him a Nobel Prize. But he was not only instrumental in working out the DNA structure with James Watson, but he then went on to do a tremendous amount of work on the genetic code and RNA, an accomplishment easily worth a second Nobel. (This part of his career is the subject of a new book by Matt Ridley, just out last month, which I plan to read at the first opportunity).
Now, clearly, the man was in the right place at the right time. But (as he himself pointed out), the key was that he realized that while it was happening. There have been any number of scientists perfectly placed to make great discoveries who failed to realize the importance of what they were (or should be) doing. An equal number have had some idea of what the stakes were, but got bogged down in one sort of mistake or another and never reached the heights they could have.
Crick seems to have had a gift for recognizing important problems that had a chance of being solved. His advice for finding these and working through them seems to me to be extremely sound. Among his recommendations are to not put too much faith in your own negative hypotheses (reasons why your ideas won't work), to not be too quick to use Occam's Razor in biology (since evolution doesn't necessarily favor simple and beautiful solutions, just ones that work), and to not fall in love with a particular model or theory to the point where you care more for it (for its own sake) than whether it's really true.
So, I can't help but wonder: how many more unrecognized Francis Cricks are out there? How many will we ever hear of? Will a person of this level always find a way to be known, or was Thomas Gray right? "Full many a flower is born to blush unseen, and waste its sweetness on the desert air". I hope not, but I fear so.
+ TrackBacks (0) | Category: Who Discovers and Why
August 3, 2006
My posts on lab photography (here and then here) stirred up comment from all over the place, split about evenly between people on either side of the camera back. Most of the scientists agreed that the shots I complained about are silly-looking, but it was correctly pointed out that if researchers who felt that way would speak up while the pictures are being taken, we'd see fewer examples of the form.
The comments from photographers, which appeared after the original posts here, on various other discussion sites and in e-mail, were more varied. Some agreed that the purple glows were an overused device, and said that they weren't using them any more. Others said that they wish that they could drop them, but that their clients (art directors and PR people) wanted things the way they usually are: bizarrely colorful. A few photographers thought that they were just fine, and a related (and larger) fourth group pretty much told me to stick to talking about things that I might have a chance of understanding.
After taking in all these suggestions, even a couple of physically implausible ones, here's my summarized take on the issue:
First off, we shouldn't necessarily blame the photographers, many of whom (as just mentioned) are giving their paying customers what they want, whether they think it's a good idea themselves or not. The observation was made, with great vigor, that publicity shots are not photojournalism.
I take the point, which was also made to me by my seven-year-old son one day when he noticed that the pictures of hamburgers on highway billboards bear little resemblance to what lands on your table down at Burger Chute. The thing is, the burger photographers are there to make the product look better, and the people who cook them presumably don't think that the billboards look completely ridiculous. Scientists, though, find the colored-spotlight school of photography laughable - but again, let's not blame the photographers. The problem lies elsewhere.
To some people, many of whom work in some form of public relations, nothing says "laboratory" quite like colored spotlights. The intention is to grab the eye, and the problem is that regular laboratory life doesn't do that very well. If we want to lose the special effects, we're going to have to either come up with a less ridiculous way to make an eye-grabbing picture, or convince the PR people that the light shows aren't doing the job. (In which case, we're going to need something to suggest in that first category anyway).
Some ideas have been offered, such as trying to get shots of real things that happen to be colorful: fluorescent TLC plates and large color-banded chromatography columns, perhaps. It's true, though, that in many labs there aren't even that many opportunities. But even getting people to switch to some of the various neon-colored disposable gloves would be less laughable than having their entire labs glowing behind them. Unusual camera angles and other compositional tricks have also been suggested, but these will always come at a cost in time and effort which may not be payable. The problem is, real art directors and brochure layout people will have to be exposed to the results of these ideas before we know if any of them are effective.
What's that? You say that perhaps we should check with the broader public who will actually be viewing the eventual brochures to see what they think? Nonsense - what do you think a public relation person's job is, if not to give the public what the PR department is sure it will like? Next!
As for convincing these folks that the standard rainbow shots aren't desirable, well, that might be a hard sell. There's an invisible line between "useful visual shorthand" and "grating stereotype", and the discussion quickly devolves into unresolvable matters of taste. For my part, I'm sure that I'm right in thinking that these shots are uselessly cheesy, but I could end up in an elevator with someone who's equally sure that they're eye-catching and effective. And science is far from the only profession to suffer from this problem, as a query to any real police officer about the realism of prime-time police dramas will make clear. It may be that in the end, we're stuck with the otherwordly glows whether we like them or not, or whether they do any good or not.
Perhaps we can even go beyond blaming the PR people and blame the whole culture (always a popular move). For hundreds of years, the image of the scientist has been only a flicker away from that of the magician. For many people, what we do in our labs might as well be sorcery for all they understand it. And how many mad scientists have haunted pulp novels and cheap movies over the years? Is it any surprise that we end up with eerie lights washing over us? What else would you expect?
+ TrackBacks (0) | Category: Life in the Drug Labs
August 2, 2006
The "Law of the Lab" I alluded to the other day is:
Yields go down faster and more unexpectedly than they go up.
My synthetic organic readers will all know what I'm talking about here. We've all had the experience of running a reaction that we've done many times before, only to find it suddenly giving half the yield that it usually does. One of the most important jobs of a process chemist is to iron things like this out, making sure that they don't happen by either tracking down the variables responsible, or ditching the reaction entirely for something more reliable.
But med-chem types like me don't always have enough time to spend on that sort of thing, so we have a lot of reactions that are in a sort of unstable equilibrium with respect to reproducibility. As long as the different factors involved - purity of the starting material, rate of addition of reagents, efficiency of heating, cooling, and stirring, etc. - are within their (sometimes narrow) green zones, things are OK. But let one or more of them wander off, and the fuses start to blow. All reactions will go to pieces on you if you push such variables too much off their mark, but the difference is that a robust one will stand up to all the variations that you'd usually encounter. A wonky reaction is just one sensitive to something that can be over the line under normal conditions.
And there sure are a lot of them. And the different chemistry that starts happening when things cut loose has a far greater chance of messing things up than it has of improving them. Most organic chemistry reactions are very artificial systems - we're using energetic reagents and conditions to make molecules go down particular paths that they wouldn't do to any useful degree by themselves. There are so many other things they can find to do otherwise, and they'll explore those pathways if they get the chance.
So while it's not completely unknown for a random variation to improve a reaction, it sure is rare. Most of them lead to yet another synthesis of the sticky brown gunk which seems to be a universal thermodynamic sink of organic chemistry. You're threading your way through a swamp of that stuff when you do synthesis, and liable to sink down into it at any moment.
+ TrackBacks (0) | Category: Lowe's Laws of the Lab
August 1, 2006
The New York Times broke the story today that the testosterone found in Tour de France champion Floyd Landis's blood was not from a natural source. Just how do they know that, and how reliable is the test?
The first thing an anti-doping lab looks for in such a case is the ratio of testosterone to the isomeric epitestosterone - too high an imbalance is physiologically unlikely and arouses suspicion. Landis already is in trouble from that reading, but the subject of the Times scoop is the isotopic ratio of the testosterone itself. And that one is going to be hard to get away from, if it's true.
Update: people are asking me why athletes don't just take extra epistestosterone to even things out. That they do - that's the most basic form of masking, and if Landis's ratio was as far off as is being reported, it's one of the odd features about this case. But the isotope test will spot either one, if it's not the kind your body produces itself - read on.
Steroids, by weight, are mostly carbon atoms. Most of the carbon in the world is the C-12 isotope, six protons and six neutrons, but around one per cent of it has an extra neutron to make it C-13. Those are the only stable isotopes of carbon. You can find tiny bits of radioactive C-14, though, and you can also get C-11 if you have access to a particle accelerator. Work fast, though, because it's hot as a pistol.
So, testosterone has 19 carbon atoms, and if on average every one out of a hundred carbon atoms is a C-13, you can calculate the spread of molecular weights you could expect, and their relative abundance. One out of every ten thousand molecules would have two C-13 atoms in there somewhere, one out of every million or so would have three, and so on. A good mass spectrometer will lay this data out for you like a deck of cards.
But here's the kicker: those isotopic forms of the elements behave a bit differently in chemical reactions. The heavier ones do the same things as their lighter cousins, but if they're involved in or near key bond-breaking or bond-making steps, they do them more slowly. It's like having a heavier ball attached to the other end of a spring. This is called a kinetic isotope effect, and chemists have found all sorts of weird and ingenious ways to expoit it. But it's been showing up for a lot longer than we've been around.
The enzymatic reactions that plants and bacteria use when they take up or form carbon dioxide have been slowly and relentlessly messing with the isotope ratios of carbon for hundreds of millions of years. And since decayed plants are food for other plants, and the living plants are food for animals, which are food for other animals and fertilizer for still more plants. . .over all this time, biological systems have become enriched in the lighter, faster-reacting C-12 isotope, while the rest of the nonliving world has become a bit heavier in C-13. You can sample the air next to a bunch of plants and watch as they switch from daytime photosynthesis to nighttime respiration, just based on the carbon isotope ratios. Ridiculously tiny variations in these things can now be observed, which have led to all sorts of unlikely applications, from determining where particular batches of cocaine came from to figuring out the dietary preferences of extinct herbivores.
So, if your body is just naturally cranking out the testosterone, it's going to have a particular isotopic signature. But if you're taking the synthetic stuff, which has been
partly worked on with abiotic forms of carbon derived from a different source (see below), the fingerprints will show. (Update: yes, this means that the difference between commercial testosterone and the body's own supply isn't as large as it would be otherwise, since the commercial synthesis generally starts from plant-derived steroid backbones. But it's still nothing that a good mass spec lab would miss). If the news reports are right, that's what Landis's blood samples have shown. And if they have, there seems only one unfortunate conclusion to be drawn.
Chem-Geek Supplemental Update: for the folks who have been wondering where exactly the isotopic difference comes in, here's the story: synthetic testosterone is made from phytosterol percursors, typically derived from wild yams or soy. Those are both warm-climate C3 plants, which take up atmospheric carbon dioxide by a different route than temperate-zone C4 plants, leading to noticeably different isotope ratios. That's where all the isotope-driven studies of diet start from. The typical Western industrial-country diet is derived from a mixture of C3 and C4 stocks, so the appearance of testosterone with a C3-plant isotopic profile is diagnostic.
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