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Insight & Intelligence : Apr 11, 2012
Review of Research with Chimpanzee Models Points to Few Areas of Need
While chimps have been used beneficially to study diseases in apes, IOM suggests their use for human diseases should be restricted.!--h2>
Last December NIH suspended all new grants for biomedical and behavioral research on chimpanzees. The agency is now working on criteria to define what type of research chimpanzees should be used for.
The guidelines emerged from a report drafted by an expert committee at the Institute of Medicine (IOM). The panel concluded that with two potential exceptions for hepatitis and mAb drug development, most research on chimpanzees was unnecessary.
If not just for the good of human health, though, chimpanzees may need to remain participants in clinical trials for their own health and survival and for the sake of other animals, as these populations continue to decline precipitously in the wild.
Past Studies Using Chimps
Historically, the participation of chimpanzees in basic biomedical research for humans has been invaluable. In the development of the Sabin oral polio vaccine, for example, Albert Sabin, M.D., evaluated hundreds of polio virus strains in “hundreds of monkeys and scores of chimps” before identifying attenuated strains that could efficiently enter the body through the digestive tract to provoke a protective immune response against different pathogenic polio strains without causing the disease themselves.
In establishing the cause of human spongiform encephalopathy, or kuru, and gaining subsequent insights into Creutzfeld-Jacob disease as well, identification of a transmissible pathogenic agent would not have been possible without chimpanzees. Multiple, early attempts to establish either kuru’s cause or transmissibility were unsuccessful. In the mid-1960s, Carleton Gajdusek, M.D., injected two chimpanzees with infected material from a child who had died of kuru. Within two years, one of the chimps developed kuru, demonstrating that the unknown disease factor was transmitted through infected biomaterial and that it could cross the species barrier to other primates.
Dr. Gajdusek was awarded the Nobel Prize in Physiology and Medicine in 1976 for showing the disease was transmissible to chimpanzees. Since that time, laboratory rodent models of spongiform encephalopathies have been successfully developed.
Hepatitis and mAb R&D
With regard to hepatitis, the chimpanzee remains the only experimental animal susceptible to infection with all five hepatitis C viruses. The chimpanzee model of HCV infection played a key role in the initial studies on non-A, non-B hepatitis, including observations on the clinical course of infection, determination of the physical properties of the virus, and eventual cloning of the HCV nucleic acid.
In 2010, IOM noted the importance of developing a preventive vaccine and that chimpanzee research will be essential in moving this work forward. Many attempts have been made to identify alternative methods to study hepatitis C infection and lifecycle. However, the chimpanzee continues to be the best model available to study all aspects of the disease including infection, viral lifecycle, immune response, and vaccine development.
To date, one human liver cell line, Huh 7, has been infectable with the virus. Experts say that the problem with this in vitro cell culture technique is that the Huh7 cell line is transformed, only slightly mimics the state of liver cells in vivo, and can only produce infectious particles of one viral isolate. These limitations place severe restrictions on the ability to understand how the virus interacts with cells and induces disease.
Chimpanzees also play a key role in developing and testing mAb-based therapies for autoimmune diseases and cancers because their cell surface receptors and cytokine profiles are almost identical to those of humans. Rituximab, which treats B-cell non-Hodgkin lymphoma, and Remicaid, approved for several inflammatory and arthritic conditions, were tested in chimpanzees.
Great Ape Diseases
Aside from their help in investigating and treating human diseases, chimpanzees have played a significant role in the development of prophylactic vaccines against diseases that kill African great apes. Each species of African great apes including chimpanzees, gorillas, and bonobos remain endangered, according to the Jane Goodall Institute. African apes are largely confined to the relatively intact forests of Equatorial Africa, and Chimpanzees are extinct in 4 of their 25 range countries (Gambia, Burkina Faso, Togo, and Benin). While these animals numbered about 1 million at the turn of the 20th century, today’s estimates put their numbers at between 172,000–300,000.
The causes for the demise of these animals include habitat loss as a result of conversion of land for agriculture, armed conflict among local human populations, and the commercial bush meat and illegal exotic pet trades. Infectious diseases also pose a serious threat. Pathogens that threaten wild gorillas and chimpanzees may be those that circulate in other forest animals (sylvatic pathogens), pathogens that spill over from humans (reverse zoonotic pathogens), and pathogens that circulate persistently within wild ape populations (enzootic pathogens).
Perhaps the best known pathogen to recently threaten African apes was (and is) the Ebola virus. Over the last two decades the Zaire strain of Ebola killed about one third of the world’s gorilla population and only a slightly smaller proportion of the world’s chimpanzees. Although these large Ebola Zaire outbreaks in great apes have been documented only in Gabon and the Republic of Congo, chimpanzees in Ivory Coast have been killed by another strain, Ebola Cote d’Ivoire.
Since many of the diseases are spilling over from humans, concern about the great ape’s vulnerability is increasing, with some advocating vaccination against common human childhood diseases.
FASEB noted in its presentation “Chimpanzee Research Helps Chimpanzees and Other Great Apes” that thousands of wild chimpanzees and gorillas have died from Ebola, which kills 95% and 77% of affected gorillas and chimpanzees, respectively. The disease alone led to a 32% decline in world populations.
Chimpanzee studies have proven invaluable in developing vaccines aimed at protecting wild apes. An ebola vaccine trial conducted in chimps in 2011 led to the development of a potential vaccine for wild gorillas, whose populations had already been reduced by a third due to the virus. The project was conducted at the New Iberia Research Center, a branch of the University of Louisiana, Lafayette with a vaccine manufactured by Integrated Biotherapeutics. The vaccine consists of a virus-like particle containing viral proteins but not the viral genome and therefore can neither be infectious nor reproduce in vivo. The vaccine was tested to determine its safety and whether it could trigger a potentially protective immune response.
Primatologist Peter Walsh, the driving force behind the experiment, ultimately wants to vaccinate wild chimpanzees and gorillas against Ebola, and he hopes this test will help get past some hurdles. “The objective is to show the conservation community that the vaccine won’t kill chimpanzees or gorillas,” he said to Science last February.
And the problem is reaching critical proportions: Apes are indeed passing the virus to each other within social groups, between social groups, and even between species. Scientists believe that control measures should be “initiated as soon as possible” to avoid the reduction of once widely distributed ape species to “tiny remnant populations.”
IOM’s 190-page report entitled “Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity” was described by NIH director Francis Collins, Ph.D., as a “thoughtful and careful analysis.” He added that “NIH will not issue any new awards for research involving chimpanzees until processes for implementing the recommendations are in place.” As those guidelines get defined, it is hoped that besides advancing drugs for human diseases, chimpanzees and other similar animals will also benefit from findings, including helping preserve wild great ape populations. Additionally, should the new guidelines restrict the use of chimps in biomedical research, well-defined rules about the ethical use of these animals should accompany them.
Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.
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