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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

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In the Pipeline

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August 1, 2004

Furry Judges, With Tails

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Posted by Derek

The phrase "guinea pig" entered the language a long time ago as slang for "test animal", but I've yet to make a compound that's crossed a guinea pig's lips. Guinea pigs are still used for a few special applications, but since the beginning of my career, I've been surrounded (metaphorically!) by rats and mice.

Of the two, I prefer the mice. That's probably because they're smaller, and need correspondingly less effort from people like me to make enough drugs to dose them. The animal-handling folks prefer them for similar reasons: rats are more ornery, and they can fetch you a pretty useful bite if they're in the mood. When I was working in Alzheimer's disease, we had a small group of elderly rats that we were checking for memory problems. If that makes you think of rat-sized rocking chairs, think again. These were big ugly customers, feisty, wily critters that knew all the tricks and were no fun to deal with. Give me mice any day.

Of course, there are mice and there are mice. "Wild-type" mice are pretty hearty, but we don't use rodents captured out in the meadow. They're too variable, not to mention being loaded down with all sorts of interesting diseases. Every rodent we use in the drug industry comes from one of the big supply houses. Even our wild-types are a particular strain, identified with a catchy moniker like "K57 Black Swiss."

You're in good shape if you can use regular animals for your drug efficacy tests, but we often work on diseases which have no good rodent equivalents. People in diabetes projects, for example, often use mutant mice such as the db/db and ob/ob strains, which are genetically predisposed to put on weight. Eventually they can show some (but not all) of the signs of Type II diabetes. They can get pretty hefty - you'd better plan on making more compound if you're going to be testing things in those guys. Meanwhile, cancer researchers go through huge number of the so-called nude mice, a nearly hairless mutant variety with a compromised immune system. You've got to know what you're doing when you have a big group of those guys, because you can imagine how a contagious rodent disease could tear through them.

All the mutant animal lines are damaged in one form or another, since they're supposed to serve as a model of a disease. (Actually, most mutants in any animal population are damaged, since in a living system it's a lot easier to make a random change for the worse than it is to make one for the better.) They're just not as robust as the wild types. They need special handling, and they can't tolerate all the methods of compound dosing that a normal animal can. In some cases, you're restricted to the mildest, tamest vehicle solutions. (You know, the ones you can't get any of your compounds to go into.)

And there's always that nagging doubt about how valid your animal models might be. Some research areas have worked out a pretty good correlation between what works in people and what works in mice, but many of us are still stumbling around. The more innovative your work, the less of an idea you have about whether you're wasting your time. 'Twas ever thus.

Comments (15) + TrackBacks (0) | Category: Animal Testing


COMMENTS

1. jsinger on August 2, 2004 11:52 AM writes...

===
"Wild-type" mice are pretty hearty, but we don't use rodents captured out in the meadow.
===

Ah, we're finally into my area of competence. To nitpick a bit:

* "Wild-type" is a genetic term, that basically is the opposite of "mutant".

* There are inbred strains of "wild" mice, as opposed to lab strains that are mostly descended from pet mice. "Hearty" is quite an understatement -- you have to work very carefully to keep them from leaping out of the cage as soon as you open them.

* There are also labs that use (quarantined) real
wild mice, mostly for behavioral tests. I understand they put the cage at the bottom of a garbage can before opening it, to keep them contained.

Permalink to Comment

2. jsinger on August 2, 2004 11:53 AM writes...

Hmmm, not sure where all my newline breaks went ...

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3. Derek Lowe on August 2, 2004 1:07 PM writes...

You're quite right - I shouldn't blend "wild" with "wild-type." It's too bad, though, that the terms are so easy to mix, considering how inbred the wild-type background strains are.

I haven't worked with the inbred wild mice that you describe, fortunately. Do they have rats like that, too? They must be a real joy.

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4. The Novice Chemist on August 2, 2004 4:14 PM writes...


I imagine that you (Derek, the chemist) don't actually dose the mice. Is your interaction with them mainly the occasional "walk down the hall" to find out how they are acting post-dosage or is your interaction more involved than that?

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5. steve on August 2, 2004 8:58 PM writes...

What is the correlation between safety/efficacy across species? I've heard cancer researchers say that if you're a rodent, we have some great cures for you, but unfortunately they don't work in people. Similarly, I've read that aspirin would not be able to get through the regulatory process today because it kills some of the animal models. Our current system will discover only drugs that work and are safe both in animals and people--we could be leaving a lot of good stuff on the table. Maybe we should be getting the NIH to give a lot more grants on differential biochemistry across species, so we'd have a better idea of which processes analogize with which models.

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6. Clay on August 3, 2004 4:23 PM writes...

Derek,

You wrote that most mutants in an animal system are damaged--are you implying that all mutations have an effect on fitness? I would have guessed that most don't, but then I really don't know too much about genetics, so maybe I don't even know what "mutant" means.

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7. jsinger on August 5, 2004 11:14 AM writes...

I don't know about wild rats (a terrifying thought, as you say) but do know an academic postdoc who works with wild squirrels he has to trap and drag into the lab. What they gain in attractiveness over rats they make up for with agility and paranoia, and apparently give some really nasty bites. Ironically -- I encountered some guinea pig data just yesterday...

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8. Greg D on August 17, 2004 9:30 PM writes...

Speaking of animal models, are there any good animal models for Parkinson's?

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9. qetzal on August 18, 2004 1:01 PM writes...

Greg D - yes, depending on what you're modeling. Treating monkeys with MPTP induces a Parkinson's-like syndrom, just as it did in the drug addicts who ingested it as a contaminant back in the 70s (I think). I understand that model has been productively used to test some PD drugs.

I'm not sure if there are good models for the progressive aspects of PD, or the levodopa-induced dyskinesias. If you're really curious, search PubMed (or even just Google).

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10. Greg D on August 18, 2004 6:29 PM writes...

So if there are animal models for Parkison's, why are we screwing around testing embryonic stem cells in humans when we can be testing them in monkeys, or rodents (found via Google)?

It's not like we have a firm grip on the science. What ever happened to figuring things out in animals, then transfering the results to humans?

Permalink to Comment

11. qetzal on August 18, 2004 8:52 PM writes...

Well, I'm not really up to date on the latest stem cell research, for PD or any other disease. But what makes you think that anyone jumps straight from a cell culture dish to a human patient?

The whole reason people are testing these things in humans is that they've already shown (some) benefit in animal models.

The only real question I can see here is whether the existing animal data is adequate to justify human tests. I don't have an informed opinion. But bear in mind, any proposed human testing goes through multiple rounds of independent review (FDA, local IRBs) before it starts. And patients must be fully informed of the risks, and participate willingly. It's not just a bunch of cowboy docs or drug developers running around unsupervised. :^)

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12. Greg D on August 27, 2004 9:34 PM writes...

But what makes you think that anyone jumps straight from a cell culture dish to a human patient?

Well, mainly because the embryonic stem cell research is still clearly "embryonic", but there's lots of screaming about how we need to fund human research, no screaming about how we need to fund animal research, yet no discussion of what we've learned from the animal research.

Is there anyone out there who is routinely curing paralyzed rats w/ rat stem cells?

Is there anyone out there who can inflict damage on rat brains, then routinely cure it with stem cells?

Is there anyone out there who can repeatedly grow any animal organ from stem cells?

Is there any reason why we (taxpayers) should fund any such research in humans, until it's successfully done in rats? (Even with the last one: the proof that you've correctly built an organ is that you can implant it in a living being, and it works correctly. You don't want to run that test in someone who suffers from a disease that has damaged the organ, because that disease may skew the results. With animals, you just remove a working organ, and replace it with your built one. Not so with humans).

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13. qetzal on August 28, 2004 12:12 AM writes...

I think the screaming is about funding to create and study human embryonic stem cell lines beyond the ones currently on Bush's approved list. Not study human embryonic stem cells in humans, but study human embryonic stem cells at all.

I agree that it's perfectly valid to question whether we've done enough in animals. The larger question of whether taxpayers should fund any given area of research is a much different point.

FWIW, there are published examples of improving Parkinson's-like symptoms in rats using embryonic stem cell lines. Here's one.

Permalink to Comment

14. Greg D on August 31, 2004 9:17 PM writes...

Ok, but the point still remains, why study human embryonic stem cell lines early in the process? You will always have greater flexibility with an animal stem cell line (perhaps I'm missing something here, but so far as I can tell the end result of any useful research involves implanting cells in a living organism, to see what happens), so why waste any money on the human lines when we still clearly don't know what we're doing?

IOW, who's pushing this, and why? Is it just pro-abortion zealots? Is there some actual scientific benefit to working with humans first? Is there a hoped for commercial benefit? If so, why aren't we requiring business to fund it?

Thanks for the pointer. Has anyone figured out how to make sure that those undifferentiated stem cells don't become bone, or hair (as I recall happened in some early Parkinson's experiments w/ humans)?

Permalink to Comment

15. kpfoley on September 5, 2004 7:13 PM writes...

Not to be anal, but it's not "K57 Black Swiss" but "C57 Black Six". Not bad for a chemist, though.

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