Ecuadorean Dwarfs May Unlock Cancer Clues

A population of dwarfs is helping researchers find new drugs to prevent cancer.

ByReporter's Notebook By JEFFREY KOFMAN
November 18, 2008, 3:08 PM

BALSAS, Ecuador, Nov. 19, 2008— -- My left hand grabs the car seat, my right hand firmly clasps the handle above the passenger door inside our rented 4-by-4. We are bouncing our way up a deeply rutted road, passing banana trees and grazing donkeys.

This is remote, rural southern Ecuador. A tropical Appalachia that until recently was cut off from the rest of the world. It seems the most unlikely of places to go in search of the cause of cancer, and maybe a cure.

Behind the wheel of the 4-by-4 is Dr. Jaime Guevara, an endocrinologist from Quito, Ecuador's capital. Almost 25 years ago, he began studying a scattered group of dwarfs in this area who have a rare disorder called Laron dwarfism, or Laron syndrome, that stunts their growth. In medical terms, their growth hormone receptors are blocked.

"There are only about 300 patients, and there are about 100 in Ecuador," says Guevara as he navigates the twisting road. "So in Ecuador you can find about one-third of the world's population with this disorder."

No Cancer Deaths, No Coincidence?

We stop at a modest cinder block building perched on a hillside. There is no glass in the windows, nothing but a few plastic chairs inside. We are welcomed into the home of Narcisa Lois and her three children. Her husband, a farm laborer who supports the family on a few dollars a day, is away at work.

Guevara is quick to point out that the smallest of the children is not the youngest. Five-year-old Yoneli stands less than 2 feet tall, 4 inches shorter than her sister. Yoneli has Laron syndrome.

The rest of the family is of normal height. Yoneli's mother had no idea that both she and her husband carried the recessive gene that randomly surfaces to cause Laron Syndrome.

"The condition needs to have the father and mother who have the mutation," explains Guevara. It is passed on through inbreeding, which is very common in this remote tropical Appalachia. There is no mystery here: Narcisa and her husband are first cousins. "Isolation, that's the whole thing," says Guevara.

Twenty years ago, when Guevara began treating and studying the dwarfs of southern Ecuador, it was because he wanted to help them. But an interesting and quirky pattern started to emerge. He realized that there has never been a single incidence of cancer or diabetes among them.

"I start noticing that somehow in this area that we all know in Ecuador is an area with high rates of cancer, not one of these patients has ever died of cancer," he says. "And I'm talking about a total of 135 names that I can think of. None of them has ever died of cancer. To me the possibility that that is a coincidence is almost none, because every single family in this case has at least one or two or three relatives that have died of cancer."

Larons Dwarfs and Longevity

Larons have historically lived extraordinarily long lives. There isn't a single community of small people here; they are scattered in towns and remote villages within 100 miles of the main city, Piñas. In these parts they are affectionately called Viejitos -- little old people -- because they appear to age prematurely.

Guevara took us to meet the oldest living Laron, an exuberant 85-year-old woman named Pastorita. Her traditional diet of farm produce has kept her healthy. Younger Larons are dying early because their small hearts can't handle the fats and cholesterol of the fast food that many prefer to eat.

We stop at a modest but well-manicured house outside the town of Balsas. Out walks Norman Apolo, normal in every sense, except he is less than 4 feet tall. He tells us he realized he had a growth disorder, at 6 or 7 years old, when was in primary school.

A husband and father of three, Apolo leads a remarkably normal life. He is a respected high school teacher and writer, and he maintains a small farm. Despite his stature, he can drive a car with extensions on the pedals.

Apolo says he was surprised to discover that there was a term for his condition.

"These are questions of nature, questions of God that I had not accepted," Apolo says. "There was always a possibility that I'd be OK."

Three hundred miles away in Quito, the capital, Guevara tracks his extraordinary patients from his offices at the Ecuador Institute of Endocrinology.

"What I routinely do is record the patients either in video or photographs, their heights, time by time," he says as he towers over four Laron patients who had come in for checkups. "This is very important, because I have documented their heights since they were kids until today."

The syndrome was first identified 40 years ago by an Israeli scientist, Dr. Zvi Laron, who saw the condition in a dozen patients in Israel and Eastern Europe.

Incredibly, it is believed the Ecuadorian Larons share a single common ancestor, probably of Jewish heritage, who fled southern Spain hundreds of years ago during the Spanish Inquisition. Generations ago they became Catholics and their heritage was forgotten. Genetic testing shows that one of the Laron dwarfs in Israel is almost certainly a distant cousin. Presumably, his ancestors fled southern Spain for Eastern Europe and then what is now Israel.

"So one of them evidently came here, brought the genetic disease with him because of inbreeding," Guevara says. "Very high inbreeding in this area because these are very isolated areas, the likelihood of a disease such as this, this disease became expressed in some people."

Scientific Applications

Working with his brother Marco, also a doctor, Guevara is studying cancer rates among the family members of normal height. While Marco collects saliva samples for genetic testing, Jaime collects case histories and data about cancer in the Laron families.

All of the findings are sent to the University of Southern California in Los Angeles, for analysis.

Long before researchers at USC knew about the Laron dwarfs in Ecuador, they simulated the exact same genetic mutation in mice. Their theory: turning off the growth hormone receptor could stop cancer from growing by blocking insulin growth factor, or IGF-1. Valter Longo, a professor at the Andrus Gerontology Center, has been working on this project for more than 15 years.

Longo found that the mice "have not only a 50 percent longer lifespan, but they also have less than 50 percent of cancer incidence. The potential application for humans is ... if we confirm that the Laron population down in Ecuador gets cancer at a reduced rate or doesn't get it at all. ? Then we know we have a pretty good evidence that this is a good way to go to prevent cancer so then we could develop drugs, which we're already doing actually, to mimic those mutations, and then use the drugs to prevent cancer."

With millions of dollars in funding from the National Institutes of Health, Longo and other scientists are now working to develop drugs that replicate the Laron mutation and stops the growth of cancer. That drug could be available within a decade. It would have taken much longer if Longo hadn't met Guevara in 2002 and learned about the Laron population in Ecuador.

"This research, the studies of the Laron could, in theory, accelerate our research by many years, maybe 20 years," says Longo. "The population allows the speeding up, because a lot of the data from mice, very clinical data, turns out to be not applicable to humans. Most drugs tested in mice fail in human trials. And now if you have strong evidence from a human population you already have a demonstration that this can work."

Longo believes that as long as the drug is given to adults, side effects could be controlled. He envisions a drug to prevent cancer that is as common as Lipitor and other statins that help prevent heart disease. But researchers still have a long way to go.

"Again, if it is confirmed that this population down in Ecuador does not get cancer or gets cancer at a reduced rate, and once we do have the drugs, and we're working very hard ... and not just us. There are several pharmaceutical companies that are working on these drugs, then these have the potential to have wide applications."

Back in Ecuador, Dr. Jaime Guevara and his patients are cooperating with USC's research.

"Over here we have this wonderful experiment of nature," says Dr. Guevara. "It's very tragic for the patients, but it's a wonderful opportunity for us the researchers, in order to understand what happens with the human body when IGF-1 is low."

When asked if he thinks this research will eventually lead to a cure for cancer, Guevara is cautious. "I am a very conservative person. The only thing I can tell you is that this thing will lead to understand a little more the phenomenon of cancer."

But there is something more Guevara and his patients want. The Larons stunted growth could easily have been normalized with regular injections of human growth hormone before adolescence. But treatment would cost tens of thousands of dollars, well beyond the means of most in a developing country like Ecuador. Drug companies have promised free drugs before but have never delivered them.

Norman Apolo insists that this is not just about finding a cure for cancer; he wants to see younger Larons given the medications they need.

"If there's a chance that we can help," Apolo says, "then yes, I am willing to participate. But I don't want to be used. I am happy to collaborate, but we don't want to be used."

It's a modest request from those who by accident of nature might help unlock the origins of cancer.