An article in The Scientist by Alison McCook tells the story of a mother whose 6-year old twins suffer from Niemann-Pick Type C (NPC) disease. The mother is petitioning the US FDA for permission to infuse a drug (cyclodextrin) directly into the twins’ brains in order to hopefully stop or control the disease. Apparently the primary basis for the mother’s decision to attempt to infuse the drug directly into the brain, it is currently being given intravenously with some limited success, is because of research with cats.
First, I want say that my heart goes out to this family, especially the mother and her daughters. NPC is a devastating disease and treatment options are very limited. It affects numerous organs and is usually lethal. My issue with situations like this generically, is because of what it appears the treatment decision was based on. McCook:
[The mother’s] optimism stems from recent findings out of Charles Vite's lab at the University of Pennsylvania, where the neuroscientist studies NPC positive cats, which typically die of the disease at 24 weeks old. But when Vite injected cyclodextrin directly into the spinal fluid of 3 NPC cats, "at 24 weeks of age, they looked clinically normal," he said. Vite is now examining their brains, and applying for an R01 to see how long the NPC cats can live when given these infusions. "I think it's kind of astonishing that giving it directly in spinal fluid has such a positive effect," Vite told The Scientist.
I am not familiar with this family’s situation and I certainly do not condemn them for trying this. NPC is a devastating and usually lethal disease. If I were in the mother’s shoes, I would probably try almost anything and I sincerely hope this works. Desperate times call for desperate measures. My issue is not with this family!
But there can be no doubt that the decision to infuse the drug directly into the brain is based on the notion that what happens in an animal models will happen in humans and this is simply not the case. (See Animal Models in Light of Evolutionfor more.) Granted, the fact that the cats were helped by this does not ipso facto mean the children will not be helped (and again I must say I sincerely hope they are), but basing a decision to proceed with a treatment on results from animals is not statistically likely to benefit the patient. Animal models simply cannot predict human drug response.
This situation exemplifies one problem with selling animal models to society based the blatantly false notion that what happens in animal will happen in humans. Humans have been and will continue to be harmed because of the vested interest groups know their research will be in jeopardy if society ever realizes how poorly animal models correlate with human response to drugs and disease. And make no mistake about it, that is how they sell animal use to society:
The majority of laboratory animal models are developed and used to study the cause, nature, and cure of human disorders . . . A third important group of animal models is employed as predictive models. These models are used with the aim of discovering and quantifying the impact of a treatment, whether this is to cure a disease or to assess toxicity of a chemical compound. (Hau 2003)
A major advantage with this in vivo system [genetically modified SCID mice] is that any data you get from SCID-hu mice is directly applicable to a human situation. (Anonymous 2008)
Zbinden writing in1991:
The three main purposes of experimental toxicology are (1) determination of the toxicological spectrum in selected laboratory animal species; (2) extrapolation to other species and prediction of adverse effects in man; and (3) determination of safe levels of exposure. (Zbinden 1991)
Biomedical sciences’ use of animals as models [is to] help understand and predict responses in humans, in toxicology and pharmacology . . . by and large animals have worked exceptionally well as predictive models for humans . . . Animals have been used as models for centuries to predict what chemicals and environmental factors would do to humans…. The use of animals as predictors of potential ill effects has grown since that time . . . If we correctly identify toxic agents (using animals and other predictive model systems) in advance of a product or agent being introduced into the marketplace or environment, generally it will not be introduced . . . The use of thalidomide, a sedative-hypnotic agent, led to some 10,000 deformed children being born in Europe. This in turn led directly to the 1962 revision of the Food, Drug and Cosmetic Act, requiring more stringent testing. Current testing procedures (or even those at the time in the United States, where the drug was never approved for human use) would have identified the hazard and prevented this tragedy. (Gad 2007) (Emphasis added.)
Fomchenko and Holland Clin Cancer Res 2006:
GEMs [genetically engineered mice] closely recapitulate the human disease and are used to predict human response to a therapy, treatment or radiation schedule . . . GEMs that faithfully recapitulate human brain tumors and will likely result in high-quality clinical trials with satisfactory treatment outcomes and reduced drug toxicities. Additional use of GEMs to establish causal links between the presence of various genetic alterations and brain tumor initiation . . . (Fomchenko and Holland 2006)
Michael F. Jacobson, executive director of the Center for Science in the Public Interest noted in 2008: “We must test animals to determine whether a substance causes cancer (CSPI 2008).” Similarly, Huff et al. observe: “Chemical carcinogenesis bioassays in animals have long been recognized and accepted as valid predictors of potential cancer hazards to humans” (Huff, Jacobson and Davis 2008).
The feline aspect of the story draws to mind the penicillin story. Prior to Florey and Chain testing penicillin systemically on humans, Fleming eventually tried it on a human because of necessity (the reason many such advances are initially applied to humans). Fleming gave it to a friend who was dying in the hospital. Weisse:
In August 1942, a close personal friend of Fleming had contracted streptococcal meningitis. When conventional therapy failed and death seemed imminent, Fleming turned to Florey for help. The latter personally delivered his remaining supply of penicillin to Flemming and instructed him in the initial use of it. A dramatic cure was obtained, even the more so since penicillin was administered into the spinal canal for the first time to enhance its effectiveness. (Weisse 1991)
Publicity surrounding Fleming’s friend led to the funding to develop the drug.
Florey, co-winner of the Nobel Prize for penicillin, administered penicillin to a cat at the same time Fleming was giving it to his sick friend. Florey’s cat died. (Allison 1974)
There is a website called What’s The Harm? that catalogues the harm from acupuncture, homeopathy, pseudoscience, the paranormal and so forth. It also promotes critical thinking and I encourage everyone to visit it. There is a great potential for harm when society believes in things that have no basis in reality.
Perhaps there are other medical research factors that went into this mother's decision that were not mentioned in the article. I hope there were and I sincerely desire the best possible outcome for this family!
Allison, V. D. 1974. Personal recollections of Sir Almroth Wright and Sir Alexander Fleming. Ulster Med J 43 (2):89-98.
Anonymous. 2008. Of Mice...and Humans. Drug Discovery and Development 11 (6):16-20.
CSPI. Longer Tests on Lab Animals Urged for Potential Carcinogens. CSPI 2008 [cited November 17. Available from http://www.cspinet.org/new/200811172.html.
Fomchenko, E. I., and E. C. Holland. 2006. Mouse models of brain tumors and their applications in preclinical trials. Clin Cancer Res 12 (18):5288-97.
Gad, SC. 2007. Preface. In Animal Models in Toxicology, edited by S. Gad: CRC Press.
Hau, Jann. 2003. Animal Models. In Handbook of Laboratory Animal Science. Second Edition. Animal Models, edited by J. Hau and G. K. van Hoosier Jr: CRC Press.
Huff, J., M. F. Jacobson, and D. L. Davis. 2008. The limits of two-year bioassay exposure regimens for identifying chemical carcinogens. Environ Health Perspect 116 (11):1439-42.
Weisse, A. B. 1991. The long pause. The discovery and rediscovery of penicillin. Hosp Pract (Off Ed) 26 (8):93-6, 101-4, 107 passim.
Zbinden, G. 1991. Predictive value of animal studies in toxicology. Regul Toxicol Pharmacol 14 (2):167-77.