Since the birth of the first “knockout mouse” in 1989, targeting and altering specific genes in mice has become one of the most common practices in genetics. By letting scientists observe the ramifications of knocking out individual genes, the technique has been crucial to interpreting the meaning of the human genome, which is 95 percent identical to our murine cousin’s. Gene targeting has allowed scientists to build models of human disease and shed light on the biological processes that make all organisms tick. (For a complete description of the technology, download this PDF.)
Earlier this week, the Nobel Assembly in Sweden recognized the importance of gene targeting by awarding the Nobel Prize in Physiology or Medicine to three scientists whose work was fundamental to its development: Mario R. Capecchi, of the University of Utah, in Salt Lake City; Martin J. Evans, of Cardiff University, in Wales; and Oliver Smithies, of the University of North Carolina at Chapel Hill. In the aftermath of the announcement, Capecchi, 70, spoke with Technology Review about the technology that won him science’s most prestigious prize and the genetic mysteries that he hopes will keep him in the lab for years to come.
Technology Review: Gene-targeting technology has shed light on myriad biological mysteries. What are some of the biggest genetics questions left to answer?
Mario Capecchi: Most genetic studies have been restricted to organisms like yeast, bacteria, worms, flies, mice, and zebrafish. The emphasis has always been on what they have in common, but I think the differences between organisms will be just as important as the similarities. Of course, it’s much more difficult to study. The differences between species of mammals or bacteria are extreme.
A graphic showing how gene targeting works.
Fortunately, we can now sequence a genome as complex as our own in a few months. It will be trivial in a few years to generate enormous amounts of genetic information on different species. What is lacking is a way to put that information in a functional framework. What do all these genetic differences mean? What makes a whale a whale and a mouse a mouse?
TR: Are you trying to answer this question in your lab?
MC: Yes. I believe a lot of evolution arises from additive mutations rather than loss of properties. A gene is duplicated in the genome, and then one copy evolves a new function while the original gene is left intact. Starting with an intact genome and adding to it, I hope what will pop out is something that was acquired in evolution.
We’ll use the mouse as a sort of surrogate to understand bats. Why can they fly and echolocate while a mouse of the same size cannot? We hope to create a collection of mice in which an entire set of bat genes is represented.
TR: Wow. How do you do that? Do you put every bat gene into different strains of mice one by one?
MC: No, that would require making approximately 25,000 mouse strains and would be much too expensive. Instead, we’ll transfer large chunks of the bat genome into mice. If we see a signal–the mice have different capabilities, for example–then we can break it down gene by gene.
TR: Why bats?
MC: They are identical in size to mice and have similar physiology, such as heart rate and body temperature. So we don’t think there will be a level of incompatibility that would kill off the mice. But we also chose bats because we know how enormously different they are from mice. Their echolocation is almost as good as our vision. They can distinguish things on a submillimeter scale.
TR: Can this approach really shed light on something as complex as echolocation, which presumably involves a lot of genes?
MC: We certainly don’t expect to make mice that can fly or echolocate. But those capabilities have individual components that we can study–the various components of the auditory system, for example.
It’s also plausible that these capabilities aren’t as complex as we thought. It’s possible to evolve very complex things with just a few genes. There are two groups of bats: megabats and microbats. People originally thought megabats evolved from primates because their brain looks more like a primate brain, while microbats’ brains look more like rodent brains. But sequencing studies show both types are related to rodents. That shows that it’s possible to develop a brain that looks histologically like ours in a very short time span.
In addition, megabats have a visual system that is more similar to ours than to rodents’. We process different aspects of the visual landscape, such as color and motion, in different parts of the brain and then somehow amalgamate it into one image. Mice have a much simpler system. Megabats are fruit eaters, and so had to discern the color of ripe fruit, just like our ancestors did. The fact that this ability evolved so quickly in bats tells me that just a handful of genes are responsible.
Of course, I’m projecting projects that will take 20 years to complete. But I’m always optimistic about the research and how long I’ll live! I think using your brain keeps you young, so I intend to keep using it.
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