Smithies' work is crucial

Colleagues 'would be years and years behind' without it

To understand the importance of Oliver Smithies' work, think of taking a cross-country trip without directions or a map. That's how basic his contributions are to medical research.

"Without his work, we'd still be groping in the dark," said Brigid Hogan, chairwoman of cell biology at Duke University Medical Center. "We would be years and years behind."

Smithies shared the Nobel Prize in medicine Monday for work that dates to 1985 when he was a professor at the University of Wisconsin.

Researchers knew that genes played a key role in human illnesses, but they couldn't pinpoint the genes or mimic the illness in animals.

"Scientists were forced to study mutant animals, basically animal freak shows," said Peter Agre, a 2003 Nobel Prize winner in chemistry.

Then Smithies developed a technique that permitted scientists to alter single, specific genes in laboratory mice. Eventually, he and others were breeding custom-made mice by genetically altering embryonic stem cells and developing them into grown animals.

The result was a leap in understanding the relationship between genes and disease. Instead of waiting to find an animal with a disease that appeared to mirror human illnesses, a "mouse model" could be created in the lab for endless study.

"The genius of this is using embryonic stem cells as a target," said Agre, vice chancellor for science and technology at Duke University Medical Center. "Then within that target you pick one specific gene out of 30,000 or so, and you obliterate it. This sort of reverse approach allows us to study individual genes."

Smithies, known for making science accessible, has compared the technique to removing a steering wheel from a car. If you don't appreciate the purpose of a steering wheel before it is removed, you can't help but understand its function once it's gone.

The technique has allowed researchers to make strides in understanding conditions such as cystic fibrosis, a life-threatening disease that allows a thick mucous to gather in the lungs. Richard Boucher, a leading cystic fibrosis researcher based at UNC-Chapel Hill, was among the first to approach Smithies about using mouse models to study the disease. By knocking out a single gene, scientists could mimic cystic fibrosis in mice.

"It was incredibly difficult," Boucher said. "I think it took them three years. It is very complex."

As expected, the diseased mice died of the same gastrointestinal problems as humans. The lungs of mice, however, were unaffected.

Discovering why a mouse's lungs do not clog with mucous brought a new focus to research. Boucher hopes it will also bring a new drug to market within two years than can be used to treat the disease.

The science of heart disease, diabetes, cancer and hypertension -- just to name a few -- have all benefited.

"They give a Nobel Prize every year in medicine, and they are all very important," Agre said. "But this is historically important. One hundred years from now people are still going to be talking about this one."