Under the Microscope: Inefficacy of Animal Models

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Under the Microscope: Inefficacy of Animal Models

By Ray Greek, MD

In order for society to stop using animals in research designed to find cures for human disease, science as a whole is going to have to acknowledge that animals and humans are dissimilar enough that the endeavor is misleading and harmful to humans. The scientific establishment includes news writers, magazines, the actual scientists using animals, scientists who do not use animals, bureaucrats, and our elected and unelected officials in Washington, DC and state governments. This is a large group and attempts to change all minds have been futile.

But things are looking up.

On September 4, 2008 a Reuters article appeared announcing: “Gene sweep may reveal new way to fight cancers. Tumors' genetic changes may point to approach to catching disease sooner.”

The Reuters article, summarizing an article appearing in Science 9/4/08, continued:

Cancer is very complex — more complex than we had believed. It is not going to be easy to develop therapies," said Dr. Bert Vogelstein of Johns Hopkins University in Baltimore and the Howard Hughes Medical Institute. "If you have 100 patients, you have 100 different diseases.

The international team sequenced the more than 20,000 genes in cells from 24 patients with advanced pancreatic cancer and from 22 patients with glioblastoma multiforme….

The findings also suggest better ways to screen for cancers, Vogelstein said.

"Our group as well as others have found that you can detect mutations outside of cells, just floating in the plasma, in virtually all patients with advanced colorectal cancer and about two-thirds of those with relatively early tumors," he said.

What this means is that everyone is different and everyone’s disease differs based on his or her genetic makeup so what works for you may not work for your sibling much less another person. Now that science is looking at human data they are finding even more reasons why animals cannot predict human response.

Sharon Begley writing in Newsweek September 6, 2008 continued this theme:

. . . cancer is on track to kill 565,650 people in the United States this year—more than 1,500 a day, equivalent to three jumbo jets crashing and killing everyone aboard 365 days a year. First [this] shows the disconnect between the bench and the bedside, between what science has discovered about cancer and how doctors treat it . . . . The meager progress has not been for lack of trying. Since 1971, the federal government, private foundations and companies have spent roughly $200 billion on the quest for cures. That money has bought us an estimated 1.5 million scientific papers, containing an extraordinary amount of knowledge about the basic biology of cancer….

Thus was born the era of chemotherapy, one that continues today. It is still based on the simple notion that disrupting DNA replication and cell division will halt cancer. Soon there would be dozens of chemo drugs that target one or more of the steps leading to cell proliferation. Almost all of those approved in the 1970s, 1980s and 1990s were the intellectual descendants of Farber's strategy of stopping cancer cells from making copies of their DNA, and then themselves, by throwing a biochemical wrench into any of the steps involved in those processes. And none of it had anything to do with understanding why cancer cells were demons of proliferation. "The clinical-research community was expending enormous effort mixing and matching chemotherapy drugs," recalls Dennis Slamon, who began a fellowship in oncology at UCLA in 1979 and is now director of clinical/translational research at the Jonsson Cancer Center there. "There was nothing coming out of the basic science that could help" patients….

It made for a lot of elegant science and important research papers. But it "all seemed to have little or no impact on the methods used by clinicians to diagnose and treat cancers," wrote Varmus. Basic-science studies of the mechanisms leading to cancer and efforts to control cancer, he observed, "often seemed to inhabit separate worlds." Indeed, it is possible (and common) for cancer researchers to achieve extraordinary acclaim and success, measured by grants, awards, professorships and papers in leading journals, without ever helping a single patient gain a single extra day of life. There is no pressure within science to make that happen. It is no coincidence that the ratio of useful therapy per basic discovery is abysmal. For other diseases, about 20 percent of new compounds arising from basic biological discoveries are eventually approved as new drugs by the FDA. For cancer, only 8 percent are.

A widely discussed 2004 article in Fortune magazine ("Why We're Losing the War on Cancer") laid the blame for this at the little pawed feet of lab mice and rats, and indeed there is a lot to criticize about animal studies. The basic approach, beginning in the 1970s, was to grow human cancer cells in a lab dish, transplant them into a mouse whose immune system had been tweaked to not reject them, throw experimental drugs at them and see what happened. Unfortunately, few of the successes in mice are relevant to people. "Animals don't reflect the reality of cancer in humans," says Fran Visco, who was diagnosed with breast cancer in 1987 and four years later founded the National Breast Cancer Coalition, an advocacy group. "We cure cancer in animals all the time, but not in people." Even scientists who have used animal models to make signal contributions to cancer treatment agree. "Far more than anything else," says Robert Weinberg of MIT, the lack of good animal models "has become the rate-limiting step in cancer research."

The August 7th edition of Nature had an excellent article (pages 682-5) on the problems of mice models of neurodegenerative diseases:

The results of drug tests in mice have never translated perfectly to tests in humans. But in recent years, and especially for neurodegenerative diseases, mouse model results have seemed nearly useless….

“I think there’s a sense of desperation that we need a convenient model for bringing drugs to clinical trial,” says Benafar. “And I do sort of hear that concern.” But desperation, he adds, is an inadequate justification for the continued use of a poor model. “It’s a bit like the proverbial drunk who keeps looking for his lost keys under the lamp post, simply because the light’s better there.”

The theme was continued in the August 2008 issue of Nature Reviews Drug Discovery:

Neurodegenerative disorders are caused by the death and dysfunction of brain cells, but despite a huge worldwide effort, no neuroprotective treatments that slow cell death currently exist. The failure of translation from animal models to humans in the clinic is due to many factors including species differences, human brain complexity, age, patient variability and disease-specific phenotypes.
Additional methods are therefore required to overcome these obstacles in neuroprotective drug development. Incorporating target validation using human brain-tissue microarray screening and direct human brain-cell testing at an early preclinical stage to isolate molecules that protect the human brain may be an effective strategy.

Animals are not humans writ small and despite the noise made by those with a vested interest in prolonging the status quo this is being noticed by society at large. Society has a long way to go but if we can help assure that society focuses on the science involved, the animals have a chance.


For more information, visit National Anti-Vivisection Society, and to see what happens to animals in laboratories, visit All-Creatures Animal Exploitation Photo Gallery.

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