Imagine a world with a cure for all chronic conditions from Alzheimer’s, cancer, and diabetes to aging. Well, that world exists — if you’re a laboratory mouse. When partaking in longevity-promoting experimentation, even some worms have lived a lifetime and a half longer than their non-tampered counterparts. Unfortunately for humans, a good chunk of these anti-aging and lifespan-prolonging approaches that work on animals don’t seem to translate to us. Many exciting biological discoveries related to altering the rate of aging in non-human species are sometimes not applicable or lost when we apply them to humans.
The move from slowing fundamental processes of aging in laboratory animals to slowing aging in humans will not be as simple as prescribing a pill and watching it work. Only after a therapeutic is confirmed as safe and effective in a preclinical model — like laboratory mice or human cells — can it be tested in people. Yet, most therapeutics don’t even make the hurdle of being safe in humans, let alone effective. A staggering 95% of drugs tested in patients fail to reach the market, despite all the promising animal studies that precede their use in humans. In the worst-case scenario, they’re deadly.
The TeGenero Incident and Other Clinical Trial Disasters
To illustrate, we can take the example of canines and chocolate. Humans are not genetically or physiologically different from dogs — our genetic compositions are roughly 84% the same; yet, we’re different enough that something we find to be a delightful dessert, like a Hershey’s bar, can be lethal for man’s best friend. That’s because dog livers are poor at breaking down a couple of chemicals found in chocolate (caffeine and theobromine). So, it doesn’t take much for toxic levels to build up in a dog’s bloodstream.
When you turn the tables on this concept, what happens is that humans can get put into dangerous situations during clinical testing; sometimes, they even die. One of the most famous examples is a clinical study conducted for an antibody called TGN1412 that preclinically demonstrated its therapeutic potential in autoimmune diseases, such as rheumatoid arthritis. In 2006, when researchers from TeGenero tested this antibody in six human volunteers, they had to immediately withdraw it from phase 1 clinical trials when six human volunteers faced life-threatening conditions involving multiorgan failure and were later moved to the intensive care unit.
In the case of TGN1412, at least part of the problem was that the drug’s target — a protein on specific immune cells — differs slightly between the monkey and human versions. The drug binds more strongly to the human immune cells and triggers a rapid release of massive amounts of chemicals involved in inflammation. Specific immune cells in mice lacked a receptor present in humans that strongly binds TGN1412, causing over-activation of the cells and the failure to predict a lethal ‘cytokine storm,’ where the immune system goes haywire, in humans.
The deadly outcome from the TGN1412 clinical study is not just a one-off event. In another clinical trial, an antiviral for Hepatitis B called Fialuridine showed adverse reactions in phase 2 clinical trials leading to the death of five human volunteers due to severe hepatic toxicity and lactic acidosis. Before being introduced into humans, Fialuridine was tested on different animals, including mice, rats, dogs, monkeys, and woodchucks. These studies demonstrated that doses hundreds of times higher than those administered to humans did not induce any toxic reactions. But none of the preclinical toxicity studies on laboratory animals could predict the toxic outcomes observed in phase II studies.
Fialuridine is toxic in humans because of a specific protein located on our mitochondria, the cell’s energy-generating structures. This protein transports the drug into the mitochondria, and once the drug is taken up, it poisons this essential cell component. This turns off the energy supply to our livers, where the drug is absorbed. Even though this protein is also present in mice, it does not send the medication into mitochondria because of only three differences in the DNA of mice. This trio of DNA mutations changes the gene encoding the protein just enough to keep it away from the cell’s mitochondria so the protein cannot transfer the drug into it.