Dr. Qi-Long Ying of USC

In the left corner, wearing the white coat, Dr. Qi-Long Ying!

Call it a Boxing Day breakthrough, research appearing in the December 26th issue of Cell could go down in history as a knockout event! For the first time, a group of scientists have derived rat embryonic stem cells, a finding that is likely to revolutionize the way we bridge the species gap between laboratory animals and humans.

For the last few decades researchers have used “knockout” mice as a model to study the genetic basis of a variety of human diseases. Knockout mice are engineered to lack a specific gene, which allows scientists to understand the normal function of that gene or the role that gene might play in a model of a particular human disease. A critical step in creating these valuable gene knockouts, is the isolation of stem cells, which was achieved in mice in 1981. The man responsible for this discovery, Martin Evans of Cardiff University in England, recently received the Nobel Prize in Medicine or Physiology for the tremendous impact the knockout method has had in developing animal models that have monumentally advanced our understanding human diseases.

In tomorrows issue of Cell, Qi-Long Ying of the University of Southern California, will demonstrate to the world that he and his colleagues have achieved what will likely become a historic feat in biomedical research, the derivation of embryonic stem cells from the laboratory rat.

Mouse, rat, what’s the difference? The goal is certainly to keep both out of the pantry, but why should we care which of these animals scientists use for knockout models? Qi-Long Ying, explains that “we know that rats are much more closely related to humans than mice in many aspects of biology.” Because of the higher level of similarity between rats and humans, rat knockout models would provide more accurate picture of the genetic causes underlying many human diseases.

So, why the long wait? It’s been 27 long years since knockouts became possible, why couldn’t the same methods used to make mouse knockouts be put to work in order to create rat knockouts? That is a tricky question to pinpoint a precise answer, but the fact remains that traditional mouse stem cell procedures have repeatedly failed in creating gene knockout rats. Failure in the knockout business occurs when isolated stem cells differentiate or mature into specific cell types, like brain cells or liver cells. This renders the cells useless for insertion into a developing mouse and thus derails the knockout process.  Researchers from USC have developed a special medium containing three important molecules that inhibit signals that normally tell the stem cells to differentiate into specific cells. Ying and his USC team have used this special medium to successfully maintain rat stem cells in their embryonic state permanently.

This is a huge advance for transgenic research, yet Dr. Qi-Long Ying points out that this is a first step for developing potentially useful rat models of human conditions. “If our work is feasible it is likely that many labs will follow up to generate different types of gene knockout rat models,” Ying explains with hope. In fact, members of the USC team are currently working on engineering the first gene knockout rat using the new, in house, embryonic stem cell method. “This will have a major impact on the future of biomedical research.” If Ying is right, he just may find himself twenty years down the line joining the list of Nobel Prize winning Laureates for creating a key tool that helped to unlock many remaining mysteries of human diseases.

While it may seem fitting that the critical finding needed to create rat knockouts should hit the presses on Boxing Day, perhaps the more intriguing coincidence is that 2008 is the Chinese year of the rat!