The Jackson Laboratory: Breeding Bad Science

What are “genetically modified mice”?

Genetically modified (GM) mice are mice whose genome has been altered in some way by experimenters. For example, a gene may have been disabled, or “knocked out.” When the gene in question is the one that produces the hormone leptin, the mice will be prone to extreme obesity. Another type of alteration involves introducing a new gene. For instance, a tumor-promoting gene could be added to the genome, making the mice very likely to develop cancer.

The Jackson Laboratory has bred and manipulated more than 7,000 strains of genetically modified mice. It was assumed that these animals would be used in research that would pave the way forward in understanding and treating human disease. However, these experiments have failed to deliver, resulting in a staggering waste of time, money, and animals’ lives.

Why has the use of GM mice in the study of human disease been ineffective?

Mice are not miniature humans. While they have organs and other body parts in common with us, the ways in which their genes function compared to ours can be quite different.

Experimenters often target a gene in a GM mouse that seems similar to the one involved in the human version of that disease. Another approach is to study a mouse gene that has been deliberately mutated so that it seems to function like a human one. But there are pitfalls with these approaches.

For example, our larger body size and longer life span mean that we experience many more DNA alterations than mice do. So forcing mutations into the shorter life span of a smaller species won’t necessarily mirror or provide insight into the ways in which these changes occur naturally in our human bodies. And important factors such as an animal’s genetic background—which can have a dramatic impact on the way a specific mutation is manifested—are often ignored.

Overall, the use of GM mice has actually hindered progress on understanding human disease, rather than helping on that front. In a recent peer-reviewed paper, scientists criticized their own profession for not recognizing this: “Although it may seem obvious that there are important differences between men and mice, this is often overlooked by those modeling human disease.”

Specifically, why have Jackson’s GM mice failed to help us understand obesity and diabetes in humans?

Jackson has developed almost 600 strains of mice for use in obesity and diabetes experiments. Myriad papers have been published on those experiments. Despite that work, many details about type 2 diabetes remain unclear. As researchers wrote in a 2014 peer-reviewed paper, “[M]eans of preventing disease progression remain elusive.” But why is this the case?

The genetic alterations most often used to induce diabetes in mice don’t even play a significant role in the human form of the disease. Moreover, rodents regulate glucose in a way that is radically different from that of humans. That fact alone makes it nearly impossible to apply experimental results in mice to humans with diabetes—and doing so can even have serious consequences.

A few years ago, experimenters found that a certain drug reduced food cravings in a strain of mice produced by Jackson. So the Food and Drug Administration approved it for human clinical trials. But it soon became apparent that the drug had serious psychiatric side effects in humans—which weren’t obvious in the initial animal experiments—and four of the patients committed suicide. The trials had to be abruptly stopped.

Despite very clear differences between humans and other species, obesity and diabetes research in animals continues, while more relevant, human-based methods are often ignored.

What about cardiovascular experiments using GM mice?

It turns out that mice who are bred in laboratories to be overweight rarely develop cardiovascular disease, unlike overweight humans—a fact that underscores the significant physiological differences between the two species.

Mice can be genetically modified to develop symptoms of cardiovascular disease—although they may not actually have the condition—and Jackson sells 834 different strains of them.

So do any of those 834 strains make for good “models” of human heart disease? In a recent large-scale analysis that evaluated 11 parameters of the heart, researchers found that just one single parameter was reasonable to use in comparisons between rodents and humans.

Heart failure experiments using animals have a particularly dismal track record. A 2015 scientific journal article put it this way: “[I]nsights gleaned from animal-based research efforts have shown poor translation in terms of deciphering human heart failure and developing effective therapies.” The paper goes on to suggest a solution: “[W]e must position our own species at center stage as the quintessential animal model for 21^st century heart failure research.”

When it comes to cardiovascular experiments on animals, the story of the drug rosiglitazone is a particularly cautionary tale. A few years ago, multiple experiments on Jackson mice found that it decreased hardening of the arteries and was useful in mitigating other cardiovascular problems. However, these experiments failed to predict that it would significantly increase the risk of bladder cancer in humans.

What is the track record on the use of GM mice in ALS experiments?

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is a progressive, degenerative illness affecting motor neurons. Mice genetically altered to develop ALS suffer from impaired coordination, severe muscle weakness, limb tremors, and paralysis.

The Jackson mouse strains most commonly used in ALS experiments have mutations that control the production of a specific protein. However, 98 percent of human ALS cases don’t involve these mutations.

So it’s not surprising that an in-depth analysis of ALS experiments using these GM mice found contradictory and ultimately useless experimental results. It also uncovered the fact that experimenters often choose not to publish studies in which treatments proved to be ineffective. The authors of the analysis warned that this bias in reporting could lead to “unnecessary (and possibly harmful) clinical trials in humans.” And that is just what happened in 2007 and 2008, when clinical ALS trials based on the “success” of compounds in Jackson mice were found to be ineffective.

In addition, a 2016 comprehensive review of ALS animal experiments warned that their results “guide researchers and resources along fruitless avenues.”

Meanwhile, experimenters have yet to develop a cure for ALS or any therapies that reverse its symptoms in human patients.

What is life like for GM mice?

GM mice commonly suffer because of the disease-like symptoms that experimenters make them endure. And their genetic modifications can also result in unintended side effects, including lameness, susceptibility to other diseases, stress, brain defects, deafness, and even death.

We must stop spending our limited public health money on this cruel and wasteful practice and instead divert it to human-relevant, non-animal methods of disease research.