In December 1988, Arlan Rosenbloom arrived in Quito, Ecuador, to treat a handful of patients. For the past decade, the endocrinologist had treated several Ecuadorian children with growth hormone deficiency, a common type of dwarfism, at his clinic at the University of Florida. Now, for the first time, he had flown down to South America to treat them at home. The plan was to give six patients their biannual dose of growth hormone, saving them the expense of visiting Rosenbloom in the States.
Once he arrived, the director of the local children’s hospital, who had previously trained under Rosenbloom, referred patients en masse, and by the end of his stay, Rosenbloom had seen 100 patients, many with growth problems. Out of the stream of patients, the ones that struck him most were two sisters, ages 6 and 8. The girls were both less than three feet tall, about the height of a typical 1-year-old.
They had prominent foreheads, piping voices, and depressed nasal bridges. But unlike Rosenbloom’s other patients, a workup showed they were not lacking growth hormone; instead, they had a rare form of dwarfism known as Laron syndrome, caused by a genetic mutation that prevents the body from respondingto growth hormone. Only a hundred or so cases of Laron syndrome had ever been diagnosed.
Once Rosenbloom returned to Florida, he wondered if and when treatment would be available to the sisters, but the syndrome itself faded from his attention. Diagnosing the occasional rare genetic disorder is part and parcel of the practice of pediatric endocrinology, and he had no reason to give the syndrome much more thought.
But by the time he returned to Ecuador to treat his growth-hormone-deficient patients six months later, one of the local endocrinologists, Jaime Guevara-Aguirre, had diagnosed another seven cases, all from the province of Loja in the south. To the two doctors conferring on the finds, the implication was obvious: If there were nine cases in one region, there were assuredly more.
Now, more than two decades later, Rosenbloom and Guevara-Aguirre’s relatively esoteric investigation into the geographical distribution of a rare genetic defect has led to one of the most remarkable discoveries ever made in modern endocrinology: a concentrated population of individuals virtually immune to cancer. The genetic defect that led to their extreme shortness of stature offered an unprecedented window into the cause and prevention of one of the world’s leading causes of death.
A natural assumption among physicians is that someone of severely short stature likely suffers from a deficiency in growth hormone, the molecule secreted by the pituitary gland that is responsible for the surge in height experienced by most children and adolescents.
But in the late 1950s, Israeli endocrinologist Zvi Laron discovered an important exception to that rule. Returning to Israel after a residency at Massachusetts General Hospital in 1957, he established the country’s first pediatric endocrinology clinic. Physicians throughout Israel began sending him patients, some with childhood diabetes and others with growth and sexual development disorders.
Laron’s earliest patients included three young siblings—two boys and a girl—with severely stunted growth. They all had the same general appearance: obese, with sparse hair, protruding forehead, and a collapsed nasal bridge. They came from a Jewish family, recently arrived in Israel from Yemen. Their grandparents were first cousins, a close connection that implied the children inherited copies of a single defective gene.
Laron assumed the simplest explanation: The siblings had a severe shortage of growth hormone. In 1963, he finally got the chance to evaluate his hypothesis with a newly developed hormonal blood test. As it turned out, the levels of growth hormone were abnormal—they were extremely high.
“We were astonished,” Laron says. “It was the exact opposite of what we expected.” His interest piqued, he scoured the region for similar cases, and by the mid-1960s he had identified 20 more. Either these people had defective hormones, Laron reasoned, or something was wrong with the cells that respond to those hormones.
Laron’s answer would come two decades later. Every cell in the body contains receptors—essentially tiny locks—on its surface. A hormone is like a microscopic key floating in the bloodstream: When it finds a matching lock, it binds to the receptor and triggers the cell to do something, such as grow or divide.
But while analyzing the liver cells of two of his patients, Laron found that normal growth hormone failed to bind to its associated receptor, suggesting that the receptors were damaged. In 1984, he published a paper showing that the short stature of people with Laron syndrome results from their inability to respond to growth hormone, no matter how much they have floating around.
One piece of the puzzle came from research by endocrinologist William Daughaday of Washington University in St. Louis. In 1956 Daughaday discovered the hormone now called insulin-like growth factor 1, or IGF-1. When growth hormone binds to a receptor, he found, it sets off a chain reaction that leads to the production of IGF-1.
It is IGF-1, not growth hormone, that stimulates the cell to grow and divide to form new cells. Damage the receptor, and there is no IGF-1 secreted and no growth. Laron worked with Daughaday to test his patients and found that while they had high levels of growth hormone, their cells were not generating IGF-1.
Over the next few decades, Laron studied more than 60 patients with the disorder that now bears his name. Half were in Israel when they were referred to him; others were referred to his clinic from a dozen countries in the Middle East, Europe, and Asia. But Laron never would have learned about the world’s largest Laron syndrome cluster had it not been for the Ecuadorian endocrinologist, Jaime Guevara-Aguirre.
Guevara-Aguirre may have been destined to study Laron syndrome. He was born in Loja province in southern Ecuador, where he often saw very short people known as pigmeitos—loosely translated as the diminutive form of pygmies—living in small towns. “I had seen maybe 20 of them on the streets when I was young,” he says.
The third of four sons of a wealthy father who owned a successful road-building company, Guevara-Aguirre never wanted to become a doctor, but it wasn’t his choice to make. His father instructed his two older brothers to become engineers, and so they did. Guevara-Aguirre and his younger brother, Marco, were sent to medical school. “We weren’t asked,” he says. “We were told to come back when we had the degree.”
Guevara-Aguirre’s studies focused on hormone receptors, and when he graduated, he told his father he wanted to create a research institute to put Ecuador on the endocrinology map. “He looked surprised, but he bought me a building and equipment to start my own institute,” Guevara-Aguirre says.
But there was one major condition: “He asked me for the name of the best medical journal. When I told him the New England Journal of Medicine, he said I had 10 years to publish a paper there or close the place. I was so nervous I couldn’t sleep for 15 days.”
Guevara-Aguirre’s Institute of Endocrinology, Metabolism, and Reproduction opened its doors in 1986. Two years later, Rosenbloom showed up, and the two became friends. When Rosenbloom returned six months later, Guevara-Aguirre had found another seven patients, all from Loja, and all with the high growth-hormone levels characteristic of Laron syndrome. The find was confirmed in summer 1989, after Rosenbloom returned to the United States with samples for analysis in the world-class lab of Stanford University endocrinologist Ron Rosenfeld.
Suspecting more Laron cases hidden in the south, Guevara-Aguirre decided he couldn’t rely on the patients to come to him. He wanted to visit the provinces of southern Ecuador, not too far from where he had spent parts of his childhood, to find more. He turned to Julio Lozada, an employee of his father’s road-building company.
Nicknamed Chispas, Spanish for sparks, Lozada was a driver—and more importantly, a skilled mechanic. Together they began making periodic trips to remote villages in Loja and the neighboring province of El Oro, using a Ford Bronco 4x4, lots of car repair tools, and a spare tire to traverse the many primitive dirt roads.
Guevara-Aguirre met with families, asked questions, and took blood samples. Every week he called Rosenbloom in Florida to tell him what they’d found: four new cases this week, three the next, and so it went. By late 1989, they had enough cases—20 total, 19 of them women—to publish an article on the “Little Women of Loja” in NEJM. Guevara-Aguirre had met his father’s demand with six years to spare.
Over the next five years, Guevara-Aguirre identified 45 more cases in Ecuador. The sex disparity evened out—men were about as likely to have Laron syndrome as women. They continued shipping blood to Rosenfeld to confirm the diagnoses. They also sent DNA samples to Stanford University geneticist Uta Francke, and in 1991 she identified a mutation in the growth hormone receptor gene in all but one of 38 patients.
The common mutation implied that all the Laron patients were probably descended from a single individual, a phenomenon known in genetics as a founder effect. At some point in the distant past, a single individual carried the genetic defect to the region and passed it to his or her children, who then passed it to their children, and on and on.
After finding that one of Laron’s patients—a Moroccan Jew—had an identical mutation to that of the Ecuadorian cohort, Rosenbloom, Guevara-Aguirre, and Laron proposed that the genetic defect for the growth hormone receptor came to Ecuador from the Iberian Peninsula five centuries before.
They theorized that the founder was a member of the conversos, a group of Spanish Jews in the 15th century who converted to Christianity under pressure and later fled during the Inquisition. Some went to Morocco and other Mediterranean countries. Others traveled to the New World and settled in the Andes Mountains, where they worked in gold mines and farms, forming part of the population comprising southern Ecuador today.
By 1994, having published several more studies in prominent medical journals, Rosenbloom and Guevara-Aguirre could have been satisfied with their once-in-a-lifetime discovery and moved on to other projects. But Guevara-Aguirre started to suspect there was more to these patients than just short stature and a genetic mutation.
As he met people, discussed their histories, and read their records, it slowly dawned on him that none of them got cancer. It was just a feeling at first, but medical journals don’t publish feelings. No one that Guevara-Aguirre spoke with was interested in pursuing the connection, and he did not have the money to do the kind of rigorous investigation that would confirm or refute his suspicion.
It took another decade for Guevara-Aguirre to find a partner who could help bring his suspicion into the mainstream: a longevity researcher at the University of Southern California named Valter Longo. Longo grew up in Italy obsessed with music and wanted to be a rock star. He came to the United States at age 16 to study jazz performance and rock, but he ended up with a biochemistry degree instead.
“I was told that I had to be in a marching band,” he explains, “and I refused to do that, and so they said I’d have to leave the program. I said, ‘Well, what else could I do in life?’ And I came up with the idea that I wanted to study aging.”
Longo’s interest in Laron syndrome, strangely enough, resulted from studying dwarf yeast. In 2001, he discovered that a strain of yeast made up of unusually small cells and colonies lived about three times longer than normal yeast and was highly protected from DNA damage and aging. The yeast cells, he found, had a mutation affecting a growth pathway similar to the defective one in Laron cases.
Longo also knew of research by molecular biologist John Kopchick at Ohio University, which showed that mice with a mutation in their growth hormone receptor gene lived 40 percent longer than normal mice—the equivalent of an average American living to age 110. “That’s the longest extension of life span ever described for a mammal,” Longo says.
Longo also had taken note of a 1990 study by University of Colorado molecular behavioral geneticist Thomas Johnson, who found roundworms with a mutation that blocked a growth pathway similar to that identified in the dwarf yeast, causing them, too, to have an increased life span.
For Longo, it all added up: The same growth genes that regulate aging and protect against age-related diseases in yeast, mice, and roundworms might have an identical effect in humans. He suspected that people with Laron syndrome, whose genetic mutation creates shortages of IGF-1, would have lower-than-usual rates of age-related diseases.
To pursue his hypothesis, Longo started out by emailing Zvi Laron himself in 2002. Could Laron please comment on the lifespan and longevity of those with the disease?
Laron pointed him to a paper he wrote on hereditary dwarfism on a remote island in Croatia. In the paper were two data points of immense interest to Longo: A couple of the subjects lived to their mid-90s. Then a colleague told Longo about Guevara-Aguirre’s work. Longo immediately looked up the Ecuadorian endocrinologist and invited him to USC to give a talk.
In April 2006, Guevara-Aguirre flew to Los Angeles and gave his presentation. People with Laron syndrome seemed to live to a ripe old age, he reported—not to age 110, but well into their 70s and 80s. He also said he didn’t recall seeing a case of cancer or hearing of anyone who had died of the disease. “That was exactly what I was hoping to hear,” Longo says. “Although obviously it was just an observation, he was their doctor, their endocrinologist.”
Longo and Guevara-Aguirre decided to work together on a survey that could confirm both their suspicions—for Longo, that the mutation revealed the secrets of longer life, and for Guevara-Aguirre, that his Laron patients had something that indeed kept cancer at bay.
“Jaime and I had to find out how much of this was true,” Longo says. He secured a small grant to do a rigorous investigation comparing cancer rates in the Laron syndrome patients with those of their relatives of normal height. After five years of fieldwork, laboratory experiments, and analysis, they reported in February 2011 that of 99 Laron syndrome cases, only one case of cancer existed on record, and that patient had survived.
By comparison, of more than 1,000 relatives of Laron patients who died during the study, one in five succumbed to cancer. The study came a couple of weeks after Laron and his colleagues published a survey of cases in the Middle East and Europe that also revealed a near-complete absence of cancer. “It seems that I was right,” Guevara-Aguirre says.
Guevara-Aguirre and Laron have differing views when it comes to connecting Laron syndrome with another deadly disease: diabetes. Although Laron has diagnosed diabetes in a handful of his patients, Guevara-Aguirre says he has never seen a case of diabetes among Laron patients in Ecuador, even though their weight should put them at high risk. In their 2011 paper, he and Longo reported that of the 99 Laron patients they studied, none had diabetes despite the prevalence of obesity in the group. In contrast, among the patients’ relatives, 5 percent of deaths were from diabetes.
Normally, people who are overweight face a greater risk for insulin resistance, a condition in which the body does not use insulin effectively to shuttle glucose into liver, fat, and muscle cells. To compensate, the pancreas secretes more insulin. In some cases, the amount of glucose in the bloodstream overwhelms the pancreas’s ability to keep up; in these cases, insulin resistance progresses to pre-diabetes or full-blown diabetes.
For people with Laron syndrome, a different set of rules seems to apply. Instead of being insulin resistant, Guevara-Aguirre’s patients seem to be especially sensitive to insulin, which may protect them against diabetes. He and Longo have recently conducted glucose-tolerance and insulin tests to explore how patients’ sensitivity to insulin affects their diabetes risk. They expect results later this year.
If the genetic mutation that gives people with Laron syndrome their short stature also protects them against two of the most pernicious diseases of aging, diabetes and cancer, then it prompts two obvious questions: What other diseases might the mutation protect against, and do people who carry the mutation in fact live longer than their unaffected peers?
The second question is more difficult to answer than it might seem because the low prevalence of cancer and diabetes in Laron patients is counterbalanced by an abnormally high risk of death from other causes, especially accidents, alcohol, and convulsive disorders.
To help untangle the question, Longo and Guevara-Aguirre are comparing mortality rates of people with Laron syndrome with their siblings to look for a noticeable difference in life expectancy. They have also begun examining whether these individuals are resistant to other aging-related killers, including cardiovascular disease and Alzheimer’s disease—both linked to dysfunctional production or metabolism of insulin and IGF-1.
Longo has also taken the first step in turning the lessons of Laron syndrome into anticancer and antiaging drugs. In 2008 he founded DSR Pharmaceuticals, where he is consulting with Kopchick to develop a pill that blocks the growth hormone receptor. They hope the drug will do artificially what the genetic defect in Laron syndrome does naturally: protect against DNA damage that fuels cancer growth.
A more expensive injection form of the drug was discovered by Kopchick a decade ago, and it has since been approved by the FDA to treat individuals with acromegaly, a condition in which there is too much growth hormone in adults, resulting in abnormal growth of body tissues, especially hands, feet, and face. Longo believes that it might be useful in the treatment of cancer and, perhaps eventually, as an antiaging supplement.
In any race to defeat cancer with a new drug, it is always wise to bet on the tumor rather than the drug. Pharmaceutical victories over cancer have been few and far between over the years. But the absence of cancer in individuals with Laron syndrome, combined with the new research on the importance of hormones such as insulin and IGF-1, suggests that the odds may soon change.
During his initial trip to Ecuador more than 24 years ago, Rosenbloom never imagined an outcome like this. “It was a phenomenal aligning of the stars,” he says. “I came to Ecuador in 1988 for another reason. Jaime had just opened his institute, and he had the road-building company to go exploring and find these people. My colleagues are very envious of my having fallen into this.”