Corante

About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png 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: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily

In the Pipeline

Category Archives

August 21, 2014

Why Not Bromine?

Email This Entry

Posted by Derek

So here's a question for the medicinal chemists: how come we don't like bromoaromatics so much? I know I don't, but I have trouble putting my finger on just why. I know that there's a ligand efficiency argument to be made against them - all that weight, for one atom - but there are times when a bromine seems to be just the thing. There certainly are such structures in marketed drugs. Some of the bad feelings around them might linger from the sense that it's sort of unnatural element, as opposed to chlorine, which in the form of chloride is everywhere in living systems.

But bromide? Well, for what it's worth, there's a report that bromine may in fact be an essential element after all. That's not enough to win any arguments about putting it into your molecules - selenium's essential, too, and you don't see people cranking out the organoselenides. But here's a thought experiment: suppose you have two drug candidate structures, one with a chlorine on an aryl ring and the other with a bromine on the same position. If they have basically identical PK, selectivity, preliminary tox, and so on, which one do you choose to go on with? And why?

If you chose the chloro derivative (and I think that most medicinal chemists instinctively would, for just the same hard-to-articulate reasons we're talking about), then what split in favor of the bromo compound would be enough to make you favor it? How much more activity, PK coverage, etc. do you need to make you willing to take a chance on it instead?

Comments (36) + TrackBacks (0) | Category: Drug Development | Odd Elements in Drugs | Pharmacokinetics | Toxicology

July 18, 2014

Thalidomide, Bound to Its Target

Email This Entry

Posted by Derek

There's a new report in the literature on the mechanism of thalidomide, so I thought I'd spend some time talking about the compound. Just mentioning the name to anyone familiar with its history is enough to bring on a shiver. The compound, administered as a sedative/morning sickness remedy to pregnant women in the 1950s and early 1960s, famously brought on a wave of severe birth defects. There's a lot of confusion about this event in the popular literature, though - some people don't even realize that the drug was never approved in the US, although this was a famous save by the (then much smaller) FDA and especially by Frances Oldham Kelsey. And even those who know a good amount about the case can be confused by the toxicology, because it's confusing: no phenotype in rats, but big reproductive tox trouble in mice and rabbits (and humans, of course). And as I mentioned here, the compound is often used as an example of the far different effects of different enantiomers. But practically speaking, that's not the case: thalidomide has a very easily racemized chiral center, which gets scrambled in vivo. It doesn't matter if you take the racemate or a pure enantiomer; you're going to get both of the isomers once it's in circulation.

The compound's horrific effects led to a great deal of research on its mechanism. Along the way, thalidomide itself was found to be useful in the treatment of leprosy, and in recent years it's been approved for use in multiple myeloma and other cancers. (This led to an unusual lawsuit claiming credit for the idea). It's a potent anti-angiogenic compound, among other things, although the precise mechanism is still a matter for debate - in vivo, the compound has effects on a number of wide-ranging growth factors (and these were long thought to be the mechanism underlying its effects on embryos). Those embryonic effects complicate the drug's use immensely - Celgene, who got it through trials and approval for myeloma, have to keep a very tight patient registry, among other things, and control its distribution carefully. Experience has shown that turning thalidomide loose will always end up with someone (i.e. a pregnant woman) getting exposed to it who shouldn't be - it's gotten to the point that the WHO no longer recommends it for use in leprosy treatment, despite its clear evidence of benefit, and it's down to just those problems of distribution and control.

But in 2010, it was reported that the drug binds to a protein called cereblon (CRBN), and this mechanism implicated the ubiquitin ligase system in the embryonic effects. That's an interesting and important pathway - ubiquitin is, as the name implies, ubiquitous, and addition of a string of ubiquitins to a protein is a universal disposal tag in cells: off to the proteosome, to be torn to bits. It gets stuck onto exposed lysine residues by the aforementioned ligase enzyme.

But less-thorough ubiquitination is part of other pathways. Other proteins can have ubiquitin recognition domains, so there are signaling events going on. Even poly-ubiquitin chains can be part of non-disposal processes - the usual oligomers are built up using a particular lysine residue on each ubiquitin in the chain, but there are other lysine possibilities, and these branch off into different functions. It's a mess, frankly, but it's an important mess, and it's been the subject of a lot of work over the years in both academia and industry.

The new paper has the crystal structure of thalidomide (and two of its analogs) bound to the ubiquitin ligase complex. It looks like they keep one set of protein-protein interactions from occurring while the ligase end of things is going after other transcription factors to tag them for degradation. Ubiquitination of various proteins could be either up- or downregulated by this route. Interestingly, the binding is indeed enantioselective, which suggests that the teratogenic effects may well be down to the (S) enantiomer, not that there's any way to test this in vivo (as mentioned above). But the effects of these compounds in myeloma appear to go through the cereblon pathway as well, so there's never going to be a thalidomide-like drug without reproductive tox. If you could take it a notch down the pathway and go for the relevant transcription factors instead, post-cereblon, you might have something, but selective targeting of transcription factors is a hard row to hoe.

Comments (9) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Chemical News | Toxicology

July 2, 2014

All Natural And Chemical Free

Email This Entry

Posted by Derek

Yesterday's link to the comprehensive list of chemical-free products led to some smiles, but also to some accusations of preaching to the choir, both on my part and on the part of the paper's authors. A manuscript mentioned in the blog section of Nature Chemistry is certainly going to be noticed mostly by chemists, naturally, so I think that everyone responsible knows that this is mainly for some comic relief, rather than any sort of serious attempt to educate the general public. Given the constant barrage of "chemical-free" claims, and what that does to the mood of most chemists who see them, some comedy is welcome once in a while.

But the larger point stands. The commenters here who said, several times, that chemists and the public mean completely different things by the word "chemical" have a point. But let's take a closer look at this for a minute. What this implies (and implies accurately, I'd say) is that for many nonscientists, "chemical" means "something bad or poisonous". And that puts chemists in the position of sounding like they're arguing from the "No True Scotsman" fallacy. We're trying to say that everything is a chemical, and that they range from vital to harmless to poisonous (at some dose) and everything in between. But this can sound like special pleading to someone who's not a scientist, as if we're claiming all the good stuff for our side and disavowing the nasty ones as "Not the kind of chemical we were talking about". (Of course, the lay definition of chemical does this, with the sign flipped: the nasty things are "chemicals", and the non-nasty ones are. . .well, something else. Food, natural stuff, something, but not a chemical, because chemicals are nasty).

So I think it's true that approaches that start off by arguing the definition of "chemical" are doomed. It reminds me of something you see in online political arguments once in a while - someone will say something about anti-Semitism in an Arab country, and likely as not, some other genius will step in with the utterly useless point that it's definitionally impossible, you see, for an Arab to be an anti-Semite, because technically the Arabs are also a Semitic people! Ah-hah! What that's supposed to accomplish has always been a mystery to me, but I fear that attempts to redefine that word "chemical" are in the same category, no matter how teeth-grinding I find that situation to be.

The only thing I've done in this line, when discussing this sort of thing one-on-one, is to go ahead and mention that to a chemist, everything that's made out of atoms is pretty much a "chemical", and that we don't use the word to distinguish between the ones that we like and the ones that we don't. I've used that to bring up the circular nature of some of the arguments on the opposite side: someone's against a chemical ingredient because it's toxic, and they know it's toxic because it's a chemical ingredient. If it were "natural", things would be different.

That's the point to drop in the classic line about cyanide and botulism being all-natural, too. You don't do that just to score some sort of debating point, though, satisfying though that may be - I try not to introduce that one with a flourish of the sword point. No, I think you want to come in with a slightly regretful "Well, here's the problem. . ." approach. The idea, I'd say, is to introduce the concept of there being a continuum of toxicity out there, one that doesn't distinguish between man-made compounds and natural ones.

The next step after that is the fundamental toxicological idea that the dose makes the poison, but I think it's only effective to bring that up after this earlier point has been made. Otherwise, it sounds like special pleading again: "Oh, well, yeah, that's a deadly poison, but a little bit of it probably won't hurt you. Much." My favorite example in this line is selenium. It's simultaneously a vital trace nutrient and a poison, all depending on the dose, and I think a lot of people might improve their thinking on these topics if they tried to integrate that possibility into their views of the world.

Because it's clear that a lot of people don't have room for it right now. The common view is that the world is divided into two categories of stuff: the natural, made by living things, and the unnatural, made by humans (mostly chemists, dang them). You even see this scheme applied to inorganic chemistry: you can find people out there selling makeup and nutritional supplements who charge a premium for things like calcium carbonate when it's a "natural mineral", as opposed (apparently) to that nasty sludge that comes out of the vats down at the chemical plant. (This is also one of the reasons why arguing about the chemist's definition of "organic" is even more of a losing position than arguing about the word "chemical").

There's a religious (or at least quasi-religious) aspect to all this, which makes the arguments emotional and hard to win by appeals to reason. That worldview I describe is a dualist, Manichean one: there are forces of good, and there are forces of evil, and you have to choose sides, don't you? It's sort of assumed that the "natural" world is all of a piece: living creatures are always better off with natural things. They're better; they're what living creatures are meant to consume and be surrounded by. Anything else is ersatz, a defective substitute for the real thing, and quite possibly an outright work of evil by those forces on the other side.

Note that we're heading into some very deep things in many human cultures here, which is another reason that this is never an easy or simple argument to have. That split between natural and unnatural means that there was a time, before all this industrial horror, when people lived in the natural state. They never encountered anything artificial, because there was no such thing in the world. Now, a great number of cultures have a "Golden Age" myth, that distant time when everything was so much better - more pure, somehow, before things became corrupted into their present regrettable state. The Garden of Eden is the aspect this takes in the Christian religion, but you find similar things in many other traditions. (Interestingly, this often takes the form of an ancient age when humans spoke directly with the gods, in whatever form they took, which is one of the things that led Julian Jaynes to his fascinating, although probably unprovable hypotheses in The Origin of Consciousness in the Breakdown of the Bicameral Mind).

This Prelapsarian strain of thinking permeates the all-natural chemical-free worldview. There was a time when food and human health were so much better, and industrial civilization has messed it all up. We're surrounded by man-made toxins and horrible substitutes for real food, and we've lost the true path. It's no wonder that there's all this cancer and diabetes and autism and everything: no one ever used to get those things. Note the followup to this line of thought: someone did this to us. The more hard-core believers in this worldview are actually furious at what they see as the casual, deliberate poisoning of the entire population. The forces of evil, indeed.

And there are enough small reinforcing bars of truth to make all of this hold together quite well. There's no doubt that industrial poisons have sickened vast numbers of people in the past: mercury is just the first one that's come to mind. (I'm tempted to point out that mercury and its salts, by the standards of the cosmetics and supplements industries, are most certainly some of those all-natural minerals, but let that pass for now). We've learned more about waste disposal, occupational exposure, and what can go into food, but there have been horrible incidents that live on vividly in the imagination. And civilization itself didn't necessarily go about increasing health and lifespan for quite a while, as the statistics assembled in Gregory Clark's A Farewell to Alms make clear. In fact, for centuries, living in cities was associated with shorter lifespans and higher mortality. We've turned a lot of corners, but it's been comparatively recently.

And on the topic of "comparatively recently", there's one more factor at work that I'd like to bring up. The "chemical free" view of the world has the virtue of simplicity (and indeed, sees simplicity as a virtue itself). Want to stay healthy? Simple. Don't eat things with chemicals in them. Want to know if something is the right thing to eat, drink, wear, etc.? Simple: is it natural or not? This is another thing that makes some people who argue for this view so vehement - it's not hard, it's right in front of you, and why can't you see the right way of living when it's so, so. . .simple? Arguing against that, from a scientific point of view, puts a person at several disadvantages. You necessarily have to come in with all these complications and qualifying statements, trying to show how things are actually different than they look. That sounds like more special pleading, for one thing, and it's especially ineffective against a way of thinking that often leans toward thinking that the more direct, simple, and obvious something is, the more likely it is to be correct.

That's actually the default way of human thinking, when you get down to it, which is the problem. Science, and the scientific worldview, are unnatural things, and I don't mean that just in the whole-grain no-additives sense of "natural". I mean that they do not come to most people as a normal consequence of their experience and habits of thought. A bit of it does: "Hey, every time I do X, Y seems to happen". But where that line of thinking takes you starts to feel very odd very quickly. You start finding out that the physical world is a lot more complicated than it looks, that "after" does not necessarily mean "because", and that all rules of thumb break down eventually (and usually without warning). You find that math, of all things, seems to be the language that the universe is written in (or at least a very good approximation to it), and that's not exactly an obvious concept, either. You find that many of the most important things in that physical world are invisible to our senses, and not necessarily in a reassuring way, or in a way that even makes much sense at all at first. (Magical explanations of invisible forces at least follow human intuitions). It's no wonder that scientific thinking took such a long, long time to ever catch on in human history. I still sometimes think that it's only tolerated because it brings results.

So there are plenty of reasons why it's hard to effectively argue against the all-natural chemical-free worldview. You're asking your audience to accept a number of things that don't make much sense to them, and what's worse, many of these things look like rhetorical tricks at best and active (even actively evil) attempts to mislead them at worst. And all in the service of something that many of them are predisposed to regard as suspicious even from the start. It's uphill all the way.

Comments (52) + TrackBacks (0) | Category: General Scientific News | Snake Oil | Toxicology

June 23, 2014

The Virtual Clinical Trial: Not Quite Around the Corner

Email This Entry

Posted by Derek

Here's one of those "Drug Discovery of. . .the. . .Future-ure-ure-ure" articles in the popular press. (I need a reverb chamber to make that work property). At The Atlantic, they're talking with "medical futurists" and coming up with this:

The idea is to combine big data and computer simulations—the kind an engineer might use to make a virtual prototype of a new kind of airplane—to figure out not just what's wrong with you but to predict which course of treatment is best for you. That's the focus of Dassault Systèmes, a French software company that's using broad datasets to create cell-level simulations for all different kinds of patients. In other words, by modeling what has happened to patients like you in previous cases, doctors can better understand what might happen if they try certain treatments for you—taking into consideration your age, your weight, your gender, your blood type, your race, your symptom, any number of other biomarkers. And we're talking about a level of precision that goes way beyond text books and case studies.

I'm very much of two minds about this sort of thing. On the one hand, the people at Dassault are not fools. They see an opportunity here, and they think that they might have a realistic chance at selling something useful. And it's absolutely true that this is, broadly, the direction in which medicine is heading. As we learn more about biomarkers and individual biochemistry, we will indeed be trying to zero in on single-patient variations.

But on that ever-present other hand, I don't think that you want to make anyone think that this is just around the corner, because it's not. It's wildly difficult to do this sort of thing, as many have discovered at great expense, and our level of ignorance about human biochemistry is a constant problem. And while tailoring individual patient's therapies with known drugs is hard enough, it gets really tricky when you talk about evaluating new drugs in the first place:

Charlès and his colleagues believe that a shift to virtual clinical trials—that is, testing new medicines and devices using computer models before or instead of trials in human patients—could make new treatments available more quickly and cheaply. "A new drug, a succesful drug, takes 10 to 12 years to develop and over $1 billion in expenses," said Max Carnecchia, president of the software company Accelrys, which Dassault Systèmes recently acquired. "But when it is approved by FDA or other government bodies, typically less than 50 percent of patients respond to that therapy or drug." No treatment is one-size-fits-all, so why spend all that money on a single approach?

Carnecchia calls the shift toward algorithmic clinical trials a "revolution in drug discovery" that will allow for many quick and low-cost simulations based on an endless number of individual cellular models. "Those models start to inform and direct and focus the kinds of clinical trials that have historically been the basis for drug discovery," Carnecchia told me. "There's the benefit to drug companies from reduction of cost, but more importantly being able to get these therapies out into the market—whether that's saving lives or just improving human health—in such a way where you start to know ahead of time whether that patient will actually respond to that therapy."

Speed the day. The cost of clinical trials, coupled with their low success rate, is eating us alive in this business (and it's getting worse every year). This is just the sort of thing that could rescue us from the walls that are closing in more tightly all the time. But this talk of shifts and revolutions makes it sound as if this sort of thing is happening right now, which it isn't. No such simulated clinical trial, one that could serve as the basis for a drug approval, is anywhere near even being proposed. How long before one is, then? If things go really swimmingly, I'd say 20 to 25 years from now, personally, but I'd be glad to hear other estimates.

To be fiar, the article does go on to mentions something like this, but it just says that "it may be a while" before said revolution happens. And you get the impression that what's most needed is some sort of "cultural shift in medicine toward openness and resource sharing". I don't know. . .I find that when people call for big cultural shifts, they're sometimes diverting attention (even their own attention) from the harder parts of the problem under discussion. Gosh, we'd have this going in no time if people would just open up and change their old-fashioned ways! But in this case, I still don't see that as the rate-limiting step at all. Pouring on the openness and sharing probably wouldn't hurt a bit in the quest for understanding human drug responses and individual toxicology, but it's not going to suddenly open up any blocked-up floodgates, either. We don't know enough. Pooling our current ignorance can only take us so far.

Remember there are hundreds of billions of dollars waiting to be picked up off the ground by anyone who can do these things. It's not like there are no incentives to find ways to make clinical trials faster and cheaper. Anything that gives the impression that there's this one factor (lack of cooperation, too much regulation, Evil Pharma Executives, what have you) holding us back from the new era, well. . .that just might be an oversimplified view of the situation.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | In Silico | Regulatory Affairs | Toxicology

June 11, 2014

Whack-A-Mole

Email This Entry

Posted by Derek

I noticed some links to this post showing up on my Twitter feed over the weekend, and I wanted to be sure to mention it. There's a recipe for "all-natural" herbicide that goes around Facebook, etc., where you mix salt, vinegar, and bit of soap, so Andrew Kniss sits down and does some basic toxicology versus glyphosate. The salt-and-vinegar mix will work, it seems, especially on small weeds, but it's more persistent in the soil and its ingredients have higher mammalian toxicity (which I'm pretty sure is the opposite of what people expect).

I hope this one makes a few people think, but I always wonder. The sorts of people who need this most are the ones least likely the read it, and the ones most likely to immediately discount it as "Monsanto shill propaganda" or the like. I had email like that last time I wrote about glyphosate (the second link above) - people asking me how much Monsanto was paying me and so on. And these people are also not interested in hearing about any LD50 data (which they probably assume is all faked, anyway). They're ready to tell you about long-term cancer and everything else (not that there's any evidence for that, either).

Going after this sort of thing is a duty, but an endless chore. I was also sent a link to an interview with some actress where she talks about her all-natural beauty regimen - so pure and green and holistic, and so very expensive, from what I could see. One of the things she advocated was clay. No, not for your skin. To eat it. It has, she explained, "negative charge" so it picks up "negative isotopes". Yeah boy. You'll have heard of those, maybe the last time you were And of course, it also picks up all those heavy metal toxins your body is swimming in, which is why a friend of hers told her that she tried the clay, and like, when she went to the bathroom it like, smelled like metal. I am not making any of this up. A few comments on that site, gratifyingly, wondered if there was any actual evidence for that clay stuff, but most of them were just having spasms of delight over the whole thing (and trading obscure, expensive sources for the all-natural lifestyle). So there's a lot of catching up to do.

Comments (27) + TrackBacks (0) | Category: Chemical News | Snake Oil | Toxicology

March 25, 2014

A New Way to Study Hepatotoxicity

Email This Entry

Posted by Derek

Every medicinal chemist fears and respects the liver. That's where our drugs go to die, or at least to be severely tested by that organ's array of powerful metabolizing enzymes. Getting a read on a drug candidate's hepatic stability is a crucial part of drug development, but there's an ever bigger prize out there: predicting outright liver toxicity. That, when it happens, is very bad news indeed, and can torpedo a clinical compound that seemed to be doing just fine - up until then.

Unfortunately, getting a handle on liver tox has been difficult, even with such strong motivation. It's a tough problem. And given that most drugs are not hepatotoxic, most of the time, any new assay that overpredicts liver tox might be even worse than no assay at all. There's a paper in the latest Nature Biotechnology, though, that looks promising.

What the authors (from Stanford and Toronto) are doing is trying to step back to the early mechanism of liver damage. One hypothesis has been that the production of reactive oxygen species (ROS) inside hepatic cells is the initial signal of trouble. ROS are known to damage biomolecules, of course. But more subtly, they're also known to be involved in a number of pathways used to sense that cellular damage (and in that capacity, seem to be key players in inducing the beneficial effects of exercise, among other things). Aerobic cells have had to deal with the downsides of oxygen for so long that they've learned to make the most of it.
isoniazid%20image.png
This work (building on some previous studies from the same group) uses polymeric nanoparticles. They're semiconductors, and hooked up to be part of a fluorescence or chemiluminescence readout. (They use FRET for peroxynitrite and hypochlorite detection, more indicative of mitochondrial toxicity, and CRET for hydrogen peroxide, more indicative of Phase I metabolic toxicity). The particles are galactosylated to send them towards the liver cells in vivo, confirmed by necropsy and by confocal imaging. The assay system seemed to work well by itself, and in mouse serum, so they dosed it into mice and looked for what happened when the animals were given toxic doses of either acetominophen or isoniazid (both well-known hepatotox compounds at high levels). And it seems to work pretty well - they could image both the fluorescence and the chemiluminescence across a time course, and the dose/responses make sense. It looks like they're picking up nanomolar to micromolar levels of reactive species. They could also show the expected rescue of the acetominophen toxicity with some known agents (like GSH), but could also see differences between them, both in the magnitude of the effects and their time courses as well.

The chemiluminescent detection has been done before, as has the FRET one, but this one seems to be more convenient to dose, and having both ROS detection systems going at once is nice, too. One hopes that this sort of thing really can provide a way to get a solid in vivo read on hepatotoxicity, because we sure need one. Toxicologists tend to be a conservative bunch, with good reason, so don't look for this to revolutionize the field by the end of the year or anything. But there's a lot of promise here.

There are some things to look out for, though. For one, since these are necessarily being done in rodents, there will be differences in metabolism that will have to be taken into account, and some of those can be rather large. Not everything that injures a mouse liver will do so in humans, and vice versa. It's also worth remembering that hepatotoxicity is also a major problem with marketed drugs. That's going to be a much tougher problem to deal with, because some of these cases are due to overdose, some to drug-drug interactions, some to drug-alcohol interactions, and some to factors that no one's been able to pin down. One hopes, though, that if more drugs come through that show a clean liver profile that these problems might ameliorate a bit.

Comments (13) + TrackBacks (0) | Category: Drug Assays | Drug Development | Pharmacokinetics | Toxicology

February 11, 2014

Pesticide Toxicity?

Email This Entry

Posted by Derek

There's been a report on the toxicity of various pesticides in the literature suggesting that they're far more toxic to human cells than had been thought. My eyebrows went up a bit when I heard this, because these sorts of assays had been done many times before. Then I realized that this was another paper from the Séralini group, and unfortunately, that alone is enough to account for the variance.

Update: commentors to this post have noted that the cell culture conditions used in the paper are rather unusual. Specifically, they're serum-free during the testing period, which puts the cells under stress to begin with. There's also the general problem, which others have brought up, about what it means to dispense these things directly onto cell cultures in diluted DMSO, since that's rather far from how they're going to be presented in the real world. Cell assays get run like that in the drug industry, to be sure, but you've got to be very careful drawing toxicological or other whole-animal conclusions from them. And we already have whole-animal studies on these formulations, don't we? I mean, juiced broccoli straight from the organic farmer's market might well have similar effects under these conditions.

Here's a story from Science with more background. Seralini is the guy who made headlines a couple of years ago with another report that genetically modified corn caused tumors in rodents, but that one was so poorly run and poorly controlled that its conclusions (which have not been seen in any other study) cannot be taken seriously. That's Séralini's problem right there: from all appearances, he's a passionate advocate for his positions, and he appears to be ready to go with whatever results line up with his beliefs. This is human nature, for sure, but science is about trying to work past those parts of human nature. The key is to keep the curious, inquisitive side, and correct for the confirmation bias I-know-I'm-right side. At this point, even if Séralini were to discover something real (and really worth taking seriously), it would have a hard time gaining acceptance, because his previous papers have been so unreliably over-the-top.

I'm not the only person who thinks that. An editor of the journal this latest Seralini paper appeared in has actually resigned because it got published:

When Ralf Reski read the latest paper from controversial French biologist Gilles-Eric Séralini, he quickly decided he wanted nothing to do with it. Séralini’s report in BioMed Research International describes how pesticides kill cultured human cells, with the hair-raising conclusion that pesticides may be vastly more toxic than assumed by regulatory authorities. Some scientists are criticizing the findings as neither surprising nor significant—but they have touched off a firestorm, with environmental groups calling for changes in how pesticides are regulated. That was too much for Reski. Within hours of reading the paper last week, the plant scientist at the University of Freiburg in Germany resigned as an editor of the journal and asked for his name to be removed from its website. "I do not want to be connected to a journal that provides [Séralini] a forum for such kind of agitation," he wrote in his resignation e-mail to the publisher, Hindawi Publishing Corporation.

Should pesticide toxicity be a subject of investigation? Absolutely. Should people be alert to assays that have not been run that should be investigated? Definitely. Are there things that we don't know about pesticide exposure that we should? I would certainly think so. But Séralini's history makes him (scientifically) one of the least effective people to be working on these questions. As a headline-grabber, though, he's pretty efficient. Which I suspect is the real point. If you're sure you're right, any weapon you can pick up is a good one.

Comments (17) + TrackBacks (0) | Category: The Scientific Literature | Toxicology

January 30, 2014

The West Virginia Formaldehyde Claim Is Nonsense

Email This Entry

Posted by Derek

This morning I heard reports of formaldehyde being found in Charleston, West Virginia water samples as a result of the recent chemical spill there. My first thought, as a chemist, was "You know, that doesn't make any sense". A closer look confirmed that view, and led me to even more dubious things about this news story. Read on - there's some chemistry for a few paragraphs, and then near the end we get to the eyebrow-raising stuff.
4-MCHM.png
The compound that spilled was (4-methylcyclohexane)methanol, abbreviated as 4-MCHM. That's its structure over there.

For the nonchemists in the audience, here's a chance to show how chemical nomenclature works. Those lines represent bonds between atoms, and if the atom isn't labeled with its own letter, it's a carbon (this compound has one one labeled atom, that O for oxygen). These sorts of carbons take four bonds each, and that means that there are a number of hydrogens bonded to them that aren't shown. You'd add one, two, or three hydrogens as needed to each to take each one up to four bonds.

The six-membered ring in the middle is "cyclohexane" in organic chemistry lingo. You'll note two things coming off it, at opposite ends of the ring. The small branch is a methyl group (one carbon), and the other one is a methyl group subsituted with an alcohol (OH). The one-carbon alcohol compound (CH3OH) is methanol, and the rules of chemical naming say that the "methanol-like" part of this structure takes priority, so it's named as a methanol molecule with a ring stuck to its carbon. And that ring has another methyl group, which means that its position needs to be specified. The ring carbon that has the "methanol" gets numbered as #1 (priority again), so the one with the methyl group, counting over, is #4. So this compound's full name is (4-methylcyclohexane)methanol.

I went into that naming detail because it turns out to be important. This spill, needless to say, was a terrible thing that never should have happened. Dumping a huge load of industrial solvent into a river is a crime in both the legal and moral senses of the word. Early indications are that negligence had a role in the accident, which I can easily believe, and if so, I hope that those responsible are prosecuted, both for justice to be served and as a warning to others. Handling industrial chemicals involves a great deal of responsibility, and as a working chemist it pisses me off to see people doing it so poorly. But this accident, like any news story involving any sort of chemistry, also manages to show how little anyone outside the field understands anything about chemicals at all.

I say that because among the many lawsuits being filed, there are some that show (thanks, Chemjobber!) that the lawyers appear to believe that the chemical spill was a mixture of 4-methylcyclohexane and methanol. Not so. This is a misreading of the name, a mistake that a non-chemist might make because the rest of the English language doesn't usually build up nouns the way organic chemistry does. Chemical nomenclature is way too logical and cut-and-dried to be anything like a natural language; you really can draw a complex compound's structure just by reading its name closely enough. This error is a little like deciding that a hairdryer must be a device made partly out of hair.

I'm not exaggerating. The court filing, by the law firm of Thompson and Barney, says explicitly:

30. The combination chemical 4-MCHM is artificially created by combining methylclyclohexane (sic) with methanol.

31. Two component parts of 4-MCHM are methylcyclohexane and methanol which are both known dangerous and toxic chemicals that can cause latent dread disease such as cancer.

Sure thing, guys, just like the two component parts of dogwood trees are dogs and wood. Chemically, this makes no sense whatsoever. Now, it's reasonable to ask if 4-MCHM can chemically degrade t