Vet Visionary

Kristina Narfstrom helps blind animals see.

by Alan Bavley

They have ever-so-cute names like Gingersnap and Cinnamon, the auburn Abyssinians from the laboratory of Kristina Narfstrom. And they have been making headlines too, even upstaging their owner at times.

Narfstrom, the University of Missouri-Columbia's Ruth M. Kraeuchi Professor in Veterinary Ophthalmology, is happy to yield the limelight, content in the knowledge that these frisky felines -- and dogs, as well -- are helping her on a career-defining mission aimed at saving the sight of millions of people with blinding retinal diseases.

Her work with dogs has led to a promising gene therapy that may one day keep children with a rare hereditary disorder from losing their vision. And the surgery she is doing to implant light-sensing microchips in the retinas of cats may help make this technology feasible for many people with deteriorating eyesight.

"This was why I got interested in being a veterinarian," Narfstrom, 59, says. "I was interested in the science and medicine. And I wanted to do something for people through the animals."

Narfstrom came to MU in 2001 from her native Sweden, where she was a leading veterinary ophthalmologist and surgeon. She brought with her seven dogs and 15 cats, progeny of the animals that have inspired much of her life's work.

Take Gingersnap, for example.

Ever since news reports began to appear early this year that Gingersnap could be turned into a "bionic cat" with a sight-saving microchip in her eye, Narfstrom has been fielding media requests for interviews from around the world.

"Cats are so...," she says, grasping for the right word. "They go straight to people's hearts."

As word of Narfstrom's work has spread, she has gotten proposals from scientists in India to collaborate on research projects. And she's received pleas from people in South Africa looking for hope that they may one day regain their vision.

The outpouring of excitement generated by Narfstrom's recent work comes as no surprise to scientists who have long followed her investigations.

"I think Kristina is one of the leaders in vision science. In veterinary ophthalmology, there are only two or three other people in the U.S. looking at things like this," says Christopher Murphy, director of the Comparative Ophthalmic Research Laboratories at the University of Wisconsin-Madison. "Kristina has contributed at many levels," Murphy says. "She's been able to follow through from the identification of hereditary problems to remediation, not just for veterinary patients, but for human patients."

The microchips that will give Narfstrom's cats their bionic eyes are part of a thriving new field of research into artificial vision that is seeking to restore sight the way the technological wizardry of cochlear implants has given a degree of hearing to the profoundly deaf.

About two dozen vision-aiding electronic devices are under development worldwide. In addition to microchips, they include video cameras mounted on eyeglasses or even implanted in the eye. Narfstrom's surgical skills had been sought by a number of the groups competing to develop bionic visual devices before she agreed to collaborate with Optobionics of Naperville, Ill.

"I considered the others' methods too invasive," she says. "Some required wires that came out of the eyes."

The Optobionics chips are tiny, just two millimeters in diameter and 37 microns thick, or about one third the thickness of a human hair. Narfstrom hopes that eventually the chips can be implanted routinely in the eyes of people with retinal diseases such as retinitis pigmentosa.

RP is a hereditary disorder that affects about one in every 4,000 people. It causes the progressive deterioration of the retina's photoreceptor cells, called rods and cones, which turn light into electrical current. As their retinal cells die, people with RP first lose peripheral and night vision, then lose their sight entirely.

Many of Narfstrom's Abyssinians have a genetic trait that leads to a condition similar to retinitis pigmentosa, making them ideal test subjects for the microchips.

The chips contain thousands of miniature solar cells that turn light into electrical current. These receptors may be able to serve as stand-ins for lost rods and cones. But early studies show that they may have even further benefits for people with RP. They seem to actually slow progression of the disease.

"It appears that there is a neuroprotective effect," Narfstrom says. "The theory is that the electrical current can stimulate growth factors in the retina so that the cells live longer."

So far, an early version of the chip has been implanted in 30 people. Published results on the first six are promising. Some of these patients found they could read more lines on an eye chart. Most could perceive colors for the first time since their vision had gone into decline; they could see the vivid green of a lawn or the bright red and white checks on a tablecloth.

The chips have continued to evolve, and that's where Narfstrom and her cats come into play. Each new generation of the chip has to be tested first on animals. Surgical techniques have to be perfected.

Narfstrom's brood of Abyssinians has been an important part of her career for the past 30 years. They have been used across the world in research projects on the structure and electrophysiology of the retina. Cinnamon, one of her Abyssinians, became a celebrity two years ago when she was selected by the National Human Genome Research Institute to be the genetic model representing house cats worldwide. Narfstrom expects the genome data assayed from the small blood and tissue samples that Cinnamon donated to be published soon.

Narfstrom discovered the cats' tendency to develop blindness quite by accident. At the time, she was living in Sweden, directing research projects for a pharmaceutical company in Stockholm. She kept a private veterinary practice on the side.

One of her patients was a 5-and-a-half-year-old male show cat that had gone blind. After examining the otherwise healthy Abyssinian, Narfstrom suspected that the cause of his blindness was hereditary. She looked at one of the kittens the cat had sired and found it had the same condition, but at an earlier stage.

The owner gave Narfstrom a female cat that became the founder of her current horde of Abyssinians. Narfstrom realized she would have to be based at a university to take full advantage of her cats' potential as a research model, so she went back to school, earning her PhD in 1985 with a dissertation that helped researchers more fully characterize the nature of the cats' retinal disorder.

The Abyssinians have a natural mutation that causes their rods and cones to die while the rest of the retina remains healthy. It's a recessive trait, meaning that offspring must inherit the gene from both parents in order to develop the condition.

At 1.5 to 2 years, they slowly but surely begin to lose vision. By 5 years old, they're blind. Most of the time, the cats can compensate for their lack of vision with other senses. "You wouldn't know that they're blind until they're really blind," Narfstrom says.

She now has more than 30 of the cats that she keeps at an animal facility on the MU campus. "I have students play and socialize with them daily. They have a very, very nice life, like home cats."

Narfstrom will be implanting the microchip in 10 of her Abyssinians. She has already tried the chips in a group of Persian cats that were blind from birth. But the Abyssinians provide a model that is closer to what people with retinitis pigmentosa may experience and thus should yield more useful data.

Tests to date show that the chips do produce electrical signals on the cats' retinas. She also has done tests to see what kinds of signals, if any, are being picked up by their brains. She's still evaluating her results and hasn't reached any conclusions yet. "We can only see that the implant is working, but we can't say what the cats are seeing," Narfstrom says.

It takes Narfstrom about 60 to 90 minutes to insert a chip into a cat's retina. Narfstrom makes two incisions into the eye, one for a light source and a second for the chip. She removes the vitreous, the clear gel inside the eye, and then uses instruments that allow her to separate the layers of the retina. She raises a small bubble in the outer layer and inserts the chip into this newly created space. Then she replaces the vitreous with a viscous substance that pushes down the bubble.

The cats recover within hours. Studies following the earliest feline surgeries, done on normal cats approximately five years ago by researchers in Atlanta, found the procedure caused no harm to the retina.

Narfstrom operates on one eye of each cat so that she can compare results to the other eye. She plans to study the Abyssinians for several years, putting them through mazes to see how well they can navigate and giving them functional MRI scans that will provide her with real-time data on how their brains are picking up visual signals.

"We are in the initial stages of this research. It will take years. But it's a start to a very exciting era," she says.

But electronics aren't the only technology that Narfstrom hopes to use. Eventually, after the gene responsible for causing the blindness in her Abyssinians is fully understood, she wants to try gene replacement therapy to restore their sight. Success with cats would pave the way for using this approach in people with RP.

Narfstrom already has had success using gene therapy to restore sight to French sheepdogs that suffer from another inherited retinal disorder. The dogs, called Briards, are born with night blindness and poor daylight vision that gets progressively worse with age.

It's a long-standing problem in this ancient breed. It was brought to Narfstrom's attention about 18 years ago when a breeder of show Briards came to her with five puppies out of a litter of nine that had obvious problems with night blindness.

The condition is very similar to Leber congenital amaurosis (LCA), a rare hereditary disorder in people. Infants with LCA may be blind at birth or lose their vision within a few years. When Narfstrom found the dogs, she recognized immediately that she might have another research model at hand. She helped organize an international effort to study the disorder.

A colleague in Germany identified the genetic defect responsible for the disorder in dogs. The gene is missing a protein that is essential to the production of rhodopsin, the pigment that triggers the retina's photoreceptors to respond to light.

The next step toward developing a gene therapy is finding a way to deliver the correct gene to the retina, where it can be incorporated into the photoreceptor cells. That delivery system often involves hitching the gene to a harmless virus that "infects" cells with the new genetic material.

With collaborators in Australia, Norway, Germany, Sweden and the United States, an innocuous adenovirus with the correct gene was constructed. The virus was then prepared at the University of North Carolina at Chapel Hill and shipped frozen in vials to Narfstrom in Columbia.

In 2001, Narfstrom began performing the delicate surgery to inject the virus into the retinas of her Briards. The results were more than just encouraging: The new genes assimilated quickly and the dogs' retinas began producing rhodopsin. "It was really great," Narfstrom says. "After three or four weeks, the dogs could see. They started to use their eyes and not just their noses."

Inspired by these results, researchers at the University of Pennsylvania are now working on clinical trials that will use the same techniques on people with LCA. "My dream now," Narfstrom says, "is to do similar studies on the [Abyssinian] cats. To me, gene transfer is one of the most exciting things."

Based on her track record, she hopes to get a research grant to support the work. "I'm just trying to gear up with money, cats and publications," she says.

Narfstrom's past successes were the reason Cecil Moore, now interim dean of the MU College of Veterinary Medicine, invited her to apply for the school's endowed chair. At the time of the offer, Narfstrom was ready for a change. She was a professor at the Swedish University of Agricultural Sciences in Uppsala, where she had risen through the ranks and served as vice dean of the veterinary college for several years.

"I realized I had come to a limit there," she says. "Their resources weren't that good. I had the opportunity here in Columbia to really continue with the [research] models I had and do something really worthwhile." So she and her husband, Stem Wiechel, a large-animal veterinarian, and their youngest son pulled up stakes and moved to Missouri.

Narfstrom has made such moves before. Growing up, she led a nomadic life as her father, a civil engineer, moved her family first to the Philippines and later to Colombia. She attended 13 different schools, sometimes two in a single year. She didn't settle in Sweden until she was 16. "I feel more international than Swedish," she says.

In her teens, Narfstrom considered becoming a doctor, but a summer job working with the ill and elderly at a nursing home discouraged her. During another summer job at a kennel, however, she was told that she had "good hands for animals," she says.

That started her thinking about a career as a veterinarian. And she's had no second thoughts: "I don't regret at all not becoming a doctor working with human patients. I think I've been able to do so much. And it's been rewarding, really."