Humankind owes a debt of gratitude to a subhuman cousin of Homosapiens named Macaca mulatta _ the rhesus monkey. This OldWorld primate donates its kidneys for culturing poliovirus hominis,needed to make poliomyelitis vaccines.
In the 1950s, when space exploration began, a rhesus monkey namedHam was the first primate launched into orbit. In parts of India today,rhesus monkeys are worshiped as sacred.
Rhesus monkeys used to lend their bodies to researchers for testingnew drugs and therapies, but their use is dwindling, because the priceof M. mulatta as an animal model of human diseases, at $1,500 to$2,000 apiece, is no longer affordable.
This downsizing is happening at the very moment that the need forone disease model in particular _ tuberculosis (TB) _ has neverbeen greater.
"The rhesus monkey was the first tuberculosis animal model," saidbacteriologist Robert Good, a guest researcher in TB at the Centersfor Disease Control and Prevention (CDC) in Atlanta. "Nobody'sused the rhesus for years," Good told BioWorld Today, "because it'svery expensive."
Last Friday, the National Institute of Allergy and Infectious Diseases(NIAID) released updated numbers on the global cost of tuberculosistoday:
* TB is the world's leading cause of death from a single infectiousorganism. It kills more adults each year than AIDS, malaria andtropical diseases combined.
* One-third of the world's population, 2 billion people, is infectedwith the TB pathogen, Mycobacterium tuberculosis. Three million ofthem a year die of it.
* Among those 2 billion are 10 million to 15 million in the U.S.,where deaths from TB now number about 2,000 annually.
A century ago "consumption," as it was then delicately called, was aleading cause of mortality in the U.S. Better hygienic standards andimproved antibacterial drug therapy during most of the 20th centurydrove TB morbidity and mortality down sharply.
TB Infection Stages Deadly Comeback In U.S.
Then, in the last 15 years or so, TB cases began to jump back up inabout 20 states, reflecting urban congestion, poor nutrition, narcotic-needle sharing and AIDS. In New York City alone, TB infectionincreased more than 100 percent. "An estimated 10 million persons inthis country," the NIAID announcement said, "are infected with theTB bacterium, and have the potential to develop active disease atsome time in their lives."
In nine out of 10 cases, M. tuberculosis lies low in the lungs, withsubclinical infection. In the remaining 10 percent, active TB erupts,causing varying degrees of breathing difficulty as the months andyears go by. In some individuals, it spreads abruptly through theblood to life-threatening tuberculosis of the eye, spine, brain or otherorgan systems.
Meanwhile, the pathogen has developed resistance to as many as sixdifferent anti-TB drugs. Diabolically, a person infected with such aresistant strain can pass it on to others by a sneeze, a cough or casualcontact.
The only vaccine against M. tuberculosis is BCG (bacille Calmette-Gurin), introduced some 70 years ago. BCG prevents the pathogenfrom spreading in the body, but not the initial infection, and has othershortcomings.
A new subunit vaccine, made from protein components of thebacterium, recently completed initial preclinical trials at theUniversity of California, Los Angeles (UCLA). There, infectious-disease researcher Marcus Horwitz and his co-workers immunizedguinea pigs with the vaccine, then sprayed TB germs into their lungs.The vaccinated animals developed one-tenth the infection level ofcontrol guinea pigs, who got only the pathogen snort.
Horwitz is now moving up from guinea pigs to primates, but notrhesus monkeys, and not in California. Rather, he has just begun totest his subunit vaccine in cynomolgus monkeys, Macaca fasicularis,at the Leonard Wood Memorial Research Center on the Philippineisland of Cebu. These animals are native to the Philippines.
But _ and it's a big but _ Horwitz did not merely assume that thecynomolgus monkeys _ although close genetic cousins of theslightly larger rhesus _ could serve as valid experimental stand-insfor human TB. First, he and microbiologist Gerald Walsh, director ofthe Cebu Center, conducted extensive trials of the Philippine animals,which they describe in the just-published April issue of NatureMedicine.
Their report bears the title: "The Philippine cynomolgus monkey(Macaca fasicularis) provides a new nonhuman primate model oftuberculosis that resembles human disease."
That resemblance involves several factors, from whether theseanimals are susceptible to TB altogether, to their response toinfection in lung, blood and other target organs, and their survival.Walsh, the paper's first author, told BioWorld Today: "We couldonly start testing the new subunit vaccine after completing this now-published study."
Cynomolgus Measures Up To Rhesus
First, the authors demonstrated that the cynomolgus is indeedsusceptible, by inoculating half a dozen animals intratracheally withextremely high doses of Mycobac-terium tuberculosis. Theydeveloped an acute and highly fatal pneumonia.
Cynomolgus susceptibility to TB was somewhat less than in rhesus,they determined, but closer than rhesus to the human condition in twoother findings:
"Monkeys challenged with lower doses of the pathogen," Walshexplained, "developed a chronic, slowly progressing, localizedpulmonary TB, akin to the disease in humans." So much so, that itfrequently extended to ocular, meningeal and spinal TB.
Equally mimicking 90 percent of human disease, which remainssubclinical, many of the low-dose cynomolgus contained theirinfection silently.
Walsh also directs the American Leprosy Foundation in Rockville,Md. He observed that his Cebu laboratory buys cynomolgus monkeysfor $450 apiece from local Philippine suppliers, "who maintain abreeding colony of some 2,000 animals." But he added: "What killsresearchers financially is not so much the initial cost as the upkeep _animal caretakers and veterinarians. In the Philippines such costs area tenth that in the U.S."
The CDC's Robert Good found the Horwitz/Walsh paper "veryexciting. It's going about developing a model of human disease in theway that it should be done," he said. "They're doing the work in thePhilippines with a monkey that's natural in that environment." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.