Knockout Mice (1500 x 977)
Photo credit: Wikipedia (public domain)

Tis the season of the Nobel, and we, ordinary mortals, should rejoice. Global warming was acknowledged as real yet again, sneering antediluvian conservatives notwithstanding. The prize for Chemistry was given for the discovery of reactions occurring on the surface of solids—which enabled the invention of none other than the iPod, among others. The prize for Economics was given for something that I really don’t understand, despite my earnest efforts. And the prize for Physiology and Medicine was given for something that sounds straight out of the boxing ring: the knockout mouse. But this is something too important to dismiss with a shrug and rolled eyes. This technology is already giving us something far more important than the iPOD—it’s a huge step forward in understanding everything about us—normal and abnormal. Sounds like a bit of a stretch? Stay tuned.


What is homologous recombination?

Chromosomes, which package DNA, exist in pairs—one inherited from each parent—and during homologous recombination, fragments of DNA can be exchanged between the two. Capecchi and Smithies (two of the three winners of the prize) found that artificial DNA of known sequence could engage in homologous recombination with mouse DNA, and exploited this to target specific mouse genes.

An artificial (synthetic) gene can do one of two things: It can be designed to knock out (or silence) a natural, also called wild type, gene. It can also be added to the genome without knocking out an existing gene.

Now this gives us a powerful tool. By knocking out a wild-type gene, we can learn about its function by observing which physiological functions are disrupted. By adding an artificial gene, we can introduce a human gene (for example, the one causing Parkinson’s disease) into a mouse, and then learn how this mutation causes the disease.

Evans, the third winner of the prize, worked out the technique that allowed the synthetic gene to be heritable. This, in essence, enabled us to create strains of mice that carried any human disease we wish to study. Thousands of strains of knock-out mice have been generated since use of the technique was first reported in 1989. More than 500 of these are models for specific human disorders such as cardiovascular and neurodegenerative diseases, and cancer.

There is literally no field of Biology and Medicine that hasn’t benefited from this powerful technology. And it brought about the new field of Genomic Medicine.


What can Genomic Medicine do for us?

The implications are almost limitless. One day, we will be able to knock out the gene causing ALS (Lou Gherig disease), or the genes predisposing to heart disease, or diabetes, or rheumatoid arthritis, or cancer. Or we’d be able to add a normal growth hormone gene to children whose short stature is genetically determined, or a normal gene to infants suffering from metabolic diseases due to some genetic deficiency.

And it doesn’t stop with Medicine. We are already creating plants that are resistant to diseases, or pests or have nutritional values that promise to wipe out hunger and malnutrition. These are the much-maligned GM (Genetically Modified) foods.

This indeed is revolutionary, and exciting. We do live in interesting times, and I, for one, feel extremely lucky.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.