Research

Research

Hepatitis Detour

Chimpanzee subjected to procedure
Chimpanzee, name unknown, subjected to a procedure
Photo: © Michael Nichols. From Brutal Kinship (Aperture)

Chimpanzees are most widely used in hepatitis C research but are also used for hepatitis A and B research. In 2006, the National Institutes of Health (NIH) spent approximately $11 million on infectious disease research. Of that amount, roughly 65% was for hepatitis C research alone. (1)

Hepatitis research on chimpanzees continues despite arguments challenging its scientific worth. As with the HIV virus, chimpanzees respond differently to being infected with the hepatitis C virus (HCV) compared to humans.

After years of research on chimpanzees costing millions of taxpayer dollars, there is still no definitive cure. However human-centered research, such as in vitro studies involving human cell cultures, is showing promising results and should therefore be pursued more aggressively on account of its greater human relevance.

About hepatitis

Hepatitis is characterized by inflammation of the liver that can be acute and self-limiting, or chronic, degenerative, and fatal. It has a variety of causes including drug and alcohol abuse, drug toxicity, and a range of viral pathogens, the most common of which are known as hepatitis A, B, or C. Typical symptoms are jaundice, fever, and liver enlargement.

Although the Hepatitis B virus (HBV) is the most prevalent of the three, the hepatitis C virus (HCV) is [in humans] “responsible for 40% of chronic liver disease in the U.S.” and “is a leading cause of liver failure and transplants.” Worldwide, over 200 million people are affected by HCV. (2) Unlike hepatitis C, hepatitis A does not lead to chronic liver infections, while hepatitis B can range from a short-term illness to a chronic one resulting in liver cancer. (3)

Hepatitis C: pathophysiology and disparities between human and chimpanzee infection

Differences between HCV infections in humans vs. chimpanzees (4)

  • The likelihood of human HCV infections becoming chronic is 75-85%; the likelihood for chimpanzees is only 30-50%.
  • Humans with HCV often develop cirrhosis of the liver, a chronic degenerative condition. Chimpanzees do not.
  • Humans with HCV frequently develop liver cancer; chimpanzees rarely do.
  • In humans, the virus can be transferred from the mother to the fetus; this does not occur in chimpanzees.

Similar to the issues with HIV chimpanzee research, these differences call into question whether or not it is likely that a vaccine for human HCV will be developed using chimpanzees—arguably, the scale of the biological differences between humans and chimpanzees underlying these observations means that chimpanzees cannot serve as a reliable and predictive model.

While studying the differences between humans and other species can inform science, it can (and has) led researchers to erroneous conclusions or dead ends. Despite its limitations, over $7 million in NIH funding was spent on HCV research involving chimpanzees in 2006. (5)

Breakthrough in cell cultures

In July 2005, hepatitis C researchers reported a breakthrough in the technology to grow the virus entirely in cell culture. (6) Increased funding should be channeled into human clinical studies and in vitro  methods of growing infectious agents for research.

The creation of a tissue culture of HCV infected human cells is important because it provides a model of the virus replicating in its “natural environment” and therefore creates a relevant system for the study of HCV pathology, and the testing of potential treatments and vaccines, in a human context.

Hepatitis B: another case of inter-species disparity

As with HCV infection, the physiology of the chimpanzees’ response differs markedly from human infection. Essentially, a chimpanzee infected with HBV will not become sick while humans exhibit traditional symptoms of liver disease. (7)

Differences between HBV infections in humans vs. chimpanzees (8)

  • Chimpanzees are essentially asymptomatic when infected; humans are not.
  • Chimpanzees continue to produce the virus as long as it is in their body; humans do not.
  • The liver, which is the organ primarily affected, is not affected in chimpanzees as it is in humans.
  • Liver enzymes, which are measured to assess the progression of the disease, respond differently in humans and chimpanzees.

Scientists commonly cite the development of the hepatitis B vaccine as an example of the essential role of chimpanzees in infectious disease research. However, the development of the hepatitis B vaccine amounted to little more than using chimpanzee bodies as “test tubes” to grow the virus—a method that has been replaced with in vitro methods. It did not come about through studying the physiology of the disease in their bodies. In actuality the first hepatitis B vaccine was made from the blood of infected humans, and vaccines are now made using genetically engineered yeast. (9)

Number of hepatitis infected chimpanzees

According to a 1997 report funded by NIH, “195 animals… participated in hepatitis virus research” at six research facilities. The report also noted, “That number substantially underestimates the total used, because of normal attrition and the fact that many chimpanzees housed at New York University’s Laboratory of Experimental Medicine and Surgery in Primates (LEMSIP)  were not counted but are known to have been used in HBV studies.” (10)

Given the number of hepatitis research protocols  currently funded by NIH—35 in 2008—an accurate number for hepatitis infected chimpanzees is unknown.

What happens to chimpanzees in hepatitis research

Hepatitis studies can be painful and grueling for chimpanzees. In addition to being isolated in sterile bio-containment facilities, the chimpanzees are subjected to frequent serial blood draws, other inoculations, and liver biopsies.

Liver biopsies are done using anesthesia and therefore require prior immobilization of the chimpanzee with a chemical agent (usually Ketamine). Lab technicians typically administer the drug to chimpanzees through a process known as “a knockdown” in which pre-loaded syringes are fired through a dart gun.

It is not unusual for a chimpanzee to be surrounded by laboratory personnel in order to be subdued or for the chimpanzee to be shot in vulnerable parts of their body—while thrashing about futilely trying to avoid the dart gun—such as their eye or genitals, or even puncturing and collapsing a lung. (Some chimpanzees have been trained to accept injections.)

Chimpanzees who have lived through these ordeals and are now in sanctuaries are living testimony to the long-term trauma such procedures cause. Fauna Foundation  in Quebec is currently home to 13 chimpanzees nearly all of whom have come out of labs. Extensive and detailed medical histories offer a window into their lives. Consider the story of Billy Jo (now deceased) as recounted by Fauna:

In 14 years at the lab, Ch-447, Billy Jo  was knocked down over 289 times—65 by dart with 4 or 5 men surrounding his cage pummeling darts into his body to anaesthetize him for a routine blood draw. In the lab he would shake his cage back and forth trying desperately to prevent anyone from approaching. To this day, Billy cannot bear to have strangers grouped in front of him.

In addition to several HIV challenges, Billy endured some 40 punch liver biopsies, 3 open wedge liver biopsies, 3 bone marrow biopsies and 2 lymph node biopsies with no tangible or practical results. He also chewed off his thumbs waking up alone from knockdowns when no one was around to care for him. During one fit of anxiety, he bit off his index finger. Anxious, aggressive, and fearful, Billy banged incessantly on his cage, rocking and staring into space when left alone. Even in sanctuary, Billy was plagued by anxiety attacks—attacks so bad that they left this majestic adult male chimpanzee choking, gagging and convulsing. (12)

In the experiment described below, published in the Proceedings of the National Academy of Sciences in 2004, three chimpanzees housed at BIOQUAL, Inc., a laboratory in Rockville, Maryland, were infected with hepatitis B and subjected to weekly liver biopsies, among other things. The study lasted 28 weeks.

Three healthy young adult HBV-seronegative [without prior infection] chimpanzees (Ch1615, -1627, and -5835) were used in this study… The animals were inoculated with 108 genome equivalents of a monoclonal HBV isolate (genotype ayw) contained in pooled serum from HBV transgenic mice. Before inoculation and weekly thereafter, blood was obtained by venipuncture and analyzed for serum alanine aminotransferase activity (sALT) as described. Six weeks after inoculation, Ch1615 and -1627 received three daily i.v. injections of either a humanized chimeric monoclonal anti-human CD4+ antibody (cM-T412) or an irrelevant control antibody, respectively, as described. The course of infection, inflammatory infiltrate, and kinetics of viral clearance were not affected in these animals… Before infection and each week thereafter, liver tissue was obtained by hepatic needle biopsy. In most instances, several tissue fragments 5 mm in length were obtained. (13)

Based on this information, we can estimate that each chimpanzee in this study was anesthetized with a dart gun 29 times during the six and a half months’ duration of the experiment. According to Fauna, “It can take up to five darts to put an adult chimp down. Some biomedical chimpanzees have been knocked down up to 220 times and have had over 130 liver biopsies done.” (14)

Hepatitis research without chimpanzees

It is claimed that chimpanzees are the only nonhuman animal capable of being infected with the virus for hepatitis C and other strains. While this may be true, it does not follow that the only way to pursue research into treatment for hepatitis is by infecting chimpanzees or that such research may lead to a cure (chimpanzees are also the only species who can be infected with the HIV virus, a point that proved irrelevant to their usefulness in HIV research.)

Examining the number of NIH funded projects for human clinical studies versus chimpanzee studies on hepatitis suggests that chimpanzee studies represent a small percentage of total studies. In 2008, NIH funded 220 human hepatitis trials (15) and only 35 research projects involving the use of chimpanzees. (16)

The millions of dollars spent on the inefficient and ineffective use of chimpanzees as “test tubes” should be channeled into developing efficient and ethical means of culturing the virus.


Sources

(1) http://report.nih.gov/index.aspx

(2) Bailey, J. (2007). A Brief Introduction to Human/Chimpanzee Biological Differences, Their Negative Impact on Research into Human Conditions, and Scientific Methods for Better and More Humane Research.

(3) http://www.cdc.gov/hepatitis/index.htm

(4) Bailey, J. (2007). A Brief Introduction to Human/Chimpanzee Biological Differences, Their Negative Impact on Research into Human Conditions, and Scientific Methods for Better and More Humane Research.

(5) http://report.nih.gov/index.aspx

(6) Lindenbach BD, Evans MJ et al, 2005. Complete Replication of Hepatitis C Virus in Cell Culture Science, July 22 309; 5734:623-626.

(7) Ibid.

(8) Bailey, J. (2007). A Brief Introduction to Human/Chimpanzee Biological Differences, Their Negative Impact on Research into Human Conditions, and Scientific Methods for Better and More Humane Research.

(9) Ibid.

(10) National Resource Council (NRC), Institute for Laboratory Animal Research (1997). Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use, Chapter 4. Washington, DC, USA: National Academy Press.

(11) http://www.sfbr.org/SNPRC/staff_bio.aspx?u=20

(12) Fauna Foundation, “Billy Jo History.” Retrieved at http://www.faunafoundation.org/english/sanct/chimps/billyjo.html

(13) Wieland S, Thimme R, Purcell RH, Chisari FV. (2004) Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA. Apr 27; 101(17): 6669-74.

(14) Fauna Foundation, “Chimpanzees in the biomedical industry.” Retrieved at http://www.faunafoundation.org/english/sanct/chimps/biomedical.html

(15) http://clinicaltrials.gov/ct2/home

(16) http://crisp.cit.nih.gov/

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