Behold the lowly armadillo, (family Dasipodidae), one of the earliestdemonstrator models of the class Mammalia.

Because armadillos are among the most primitive of mammals, theyare not exactly cold-blooded, but cool-blooded. Their bloodcirculates at several degrees below the normal body temperaturerange of modern mammals.

This feature explains why armadillos also are among the mostprimitive of medical animal models. Fittingly, the disease for whichthey act as surrogates _ leprosy _ is one of the oldest ills to afflictthe human race.

Mycobacterium leprae is the pathogen that causes leprosy. Itmultiplies at temperatures well below the human norm, which is whyfor decades leprologists have made armadillos their animal model ofchoice, culturing M. leprae organisms in their blood as an aid todiagnosis and monitoring.

Specialists in other diseases have been less lucky. Diabetesresearchers, to cite a typical example of serendipity, several years agodiscovered by chance a naturally mutated obese mouse.

Then in 1988, Harvard's Philip Leder patented the celebratedHarvard oncomouse for modeling innate malignancies. Since which,transgenic rodents and other subhuman mammals have made made-to-order, disease-specific animal models a growth industry.

To be sure, there have been some stubborn hold-outs, notably AIDS.Subhuman primates simply don't evoke the natural history of HIVinfection, and if they did, cost and their lengthy life expectancywould make them impractical.

And Now, Atherosclerosis

Another elusive animal model on which industry and academia arefocusing intently is atherosclerosis.

Coronary heart disease leads all other causes of mortality indeveloped nations. Its twin smoking guns are low-densitylipoproteins (LDL) and cholestyrl ester transfer protein (CETP).Between them, these two molecules conspire to build up cholesterolin the blood to form the artery-damming plaques of atherosclerosis,which, with fatal effect, cut off blood supply to the heart. (SeeBioWorld Today, May 17, 1995, p. 1.)

High-density lipoproteins (HDL), on the other hand, take the playaway from LDLs by detouring excess cholesterol to the liver foreventual excretion from the body.

Too much fat in the diet, and too little exercise in the lifestyle, stackthe deck in favor of the LDL cholesterol loaders. That's why, so thesupposition goes, humanity's hunter-gatherer progenitors grew uplean and serene _ cardiologically speaking _ bereft of high-fatfoods and TV sloth, and high on HDLs.

That too is why laboratory mice tend to park most of their cholesterolin HDLs. If that's all that atherosclerosis involved _ a simpletension between high- and low-density lipoproteins, then low-cost,short-lived, high-birth rate mice would make ideal animal models forscreening drugs to lower cholesterol.

But the three-way stand-off involving LDLs, HDLs and CETP is farmore complex, and so far there hasn't been a satisfactory rodentsurrogate. So far, but no farther.

This month's Journal of Lipid Research (May 1995) carries an articletitled: "Transgenic mice expressing both human apolipoprotein B andhuman CETP have a lipoprotein cholesterol distribution similar tothat of normolipidemic humans." Its principal author is molecularbiologist Mark Swanson, director of transgenic sciences at DNXCorp.'s Princeton, N.J. facility.

First, Swanson and his co-authors microinjected the gene forapolipoprotein B, which elevates HDL levels, into early embryoniccells, and raised a second-generation colony of rodents expressingthese lipoproteins.

Second, they inserted the gene for human CETP into other mouseeggs, to obtain transgenics expressing this human gene, whichperversely lowers HDLs.

Third, they mated the two strains together, and now have "over ahundred of these double transgenic mice," Swanson told BioWorldToday, "and still counting."

DNX is now offering these mouse models, with cholesterol-handlingsystems in the image of humans, to researchers seeking to discover orsynthesize compounds that will tilt the balance in heart-disease-pronepatients in favor of HDLs, against LDLs.

"We make the mice available through our subsidiary, PharmakonResearch International," Swanson said. "located in Waverly, Pa. andLyon, France. There, people can have their compounds screened orevaluated. And we're working on licensing arrangements for actuallyhanding over animals to investigators who want to bring them intotheir own facility."

In normal lab animals, fed a high-cholesterol diet to induceatherosclerosis, Swanson noted in his published paper, "females tendto be somewhat more susceptible than males." The opposite prevailsin the human condition, he added. "Age onset is critical: Men aregenerally more prone to developing atherosclerosis a good ten yearssooner than women."

Do DNX Mice Actually Develop Atherosclerosis?

DNX constructed its triple-threat, human-mimicking mice last year. Iffed a high-cholesterol diet, should some of them by now be showingthe signs of arterial plaque build-up?

"We have the data," Swanson said, "but we don't want to jeopardizepublication by talking about it yet."

He will be ready to talk come November, in a presentation to eitherthe American Heart Association, meeting in Anaheim, Calif., or aconference on Drugs Affecting Lipid Metabolism in Houston.

If it turns out that these transgenic mice actually do developatherosclerosis, the same as folks do, how then would they be used?

"Once we demonstrate that they have the disease, Swanson replied,"we could do longer term studies to look at efficacy in terms ofreversing atherosclerosis, instead of just lowering lipid levels. Thatwould more likely be done not as screening, but to validate analready interesting drug, to really measure the endpoint that you'relooking for _ reduction of atherosclerotic plaque." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.