This article was taken from the October 2014 issue of Wired magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content by subscribing online.
Medical research has had remarkable success in finding new drugs for various diseases. Over the last 50 years, multiple types of cancer, atherosclerosis, autoimmune diseases and many others have been successfully treated... in mice.
The problem is that few of these treatments translated successfully into humans. The main approach to developing medical
drugs today consists of using mouse models to test molecules that are successful candidates in test-tube experiments. Some advantages of mice for such screening include their size, cost, convenience and the easy ability to manipulate them genetically. Every year, billions of dollars are spent in drug development by pharmaceutical companies using this approach.
However, only a very small percentage of drugs that work in mice end up being licensed for use in humans.
One of the problems with this model of drug development is the assumption that the disease induced in mice is the same as in humans. This premise might be wrong. Consider inflammation. It occurs during infection as the immune system in our body detects and reacts to a microbe in an attempt to get rid of it. Ironically, however, this inflammatory response causes damage to tissues. When the inflammation is severe and generalised, it is called severe sepsis, a syndrome that likely affects millions of patients each year. More than a quarter of these patients die.
Humans are very sensitive to most inflammatory stimuli, whereas mice are highly resistant to the very same stimuli. Indeed, mice are about 10,000-fold more resistant than humans to endotoxin, which is one of the most common pro-inflammatory bacterial toxins used to study inflammation. Unlike humans, mice tolerate millions of live bacteria in their blood before the induction of severe inflammation or shock. Some recent work suggests that the gene responses of mice to inflammatory stimuli may be different from those in humans. A recent large-scale study compared the individual gene responses in three human conditions (acute trauma, acute burns and injection of tiny amounts of endotoxin into volunteers) with the mouse models used to study these conditions. There was very poor correlation of gene responses in the two species. This study undermines the current widespread assumption that mice are good models for human inflammatory diseases. Inflammation is an essential component of many diseases, including cancer, atherosclerosis and autoimmune diseases, so it seems likely that the two species may differ in gene responses to these diseases as well.
Because most researchers have been assuming that mice and humans have similar immune systems, we still know very little about why the species react differently to disease. In general, immune cells from mice and humans behave similarly when studied in test-tube cell-culture systems. However, their different responses become manifest in mice or humans in vivo. It therefore seems possible that part of the species difference may reflect the way immune cells are controlled.
By way of analogy, such a difference would be akin to a difference in the "software" rather than in the "hardware" of the immune system. Mice have a high natural resistance to inflammation whereas humans do not -- in many situations mice behave as if already treated. Once we have a better understanding of these differences, the solution might then be to emulate mice rather than use them as a poor proxy for humans. Indeed, it may be possible to re-programme human inflammatory and immune responses to become more like those in mice.
Shaw Warren is a physician-researcher at Massachusetts General Hospital's Infectious Disease Unit and Harvard Medical School, Boston, Massachusetts. More information regarding the approach outlined in this article is available at massgeneral.org/id/labs/warren/spirit
This article was originally published by WIRED UK
