It was like watching the pieces of a puzzle assemble: Could this gene, found on the same chromosome that defines Down syndrome, be especially bountiful in people with Down and, thus, responsible for depriving tumors of what they need to grow?

At the same time, experiments were showing that the gene had a significant effect in stanching the growth of blood vessels that nourish tumors.

That changed soon enough when Ryeom recognized where that gene lives in the human body: on chromosome 21. That is the same chromosome that exists in triplicate in people with Down syndrome. Most people inherit chromosomes in pairs. But it is the third chromosome 21 that produces the external physical features and internal medical problems associated with Down syndrome, including heart defects, respiratory problems, and Alzheimer's disease.

"At that point," Ryeom said, "it was not looked at in terms of cancer, blood vessel growth, or Down syndrome."

Six years ago, Ryeom and other scientists identified the genetic mechanism that acts like an on-and-off switch for calcineurin.

As a junior researcher, Sandra Ryeom wanted to better understand a protein called calcineurin - and, more specifically, what controls its activity in humans. It was a subject of intense interest because the protein plays a sometimes lethal role in causing transplanted organs to be rejected by recipients.

In many respects, the discovery, detailed last month in the journal Nature, is a textbook example of scientific serendipity.

"Most people don't appreciate the fact that these individuals with Downs potentially hold a secret that might lead to quite substantial and revolutionary new treatments for cancer," said Dr. David Sweetser, who treats patients and researches cancer at MassGeneral Hospital for Children but was not involved in the Downs project. "The obvious hope is that this is going to give us information to help develop a tool that we could use to treat a whole variety of solid tumors."

The scientists discovered that the extra chromosome carried by people with Down syndrome - which causes the condition's distinctive features - harbors a gene responsible for starving tumors of the blood they need to survive and flourish.

Now, 17 months after he died, researchers in his lab at Children's Hospital Boston have found an answer, and their discovery could provide a beacon to scientists developing treatments and preventive medications designed to be broadly effective against cancer, wherever it resides in the body.

The famed Boston scientist Judah Folkman puzzled over the question for decades, since encountering it on an exam as a young medical student.

It is a scientific riddle that has stumped, and deeply intrigued, specialists in cancer and genetics for decades: Why do people with Down syndrome so rarely develop life-threatening tumors?

Epidemiologic studies of thousands of people with Down syndrome - there are more than 400,000 in the United States - have shown they are less than 10 percent as likely to die from solid tumors as their comparably aged peers, and that has remained true even as scientific advances allow people with the syndrome to live deeper into adulthood. Curiously, though, Down syndrome appears to increase prospects of being diagnosed with leukemia, a blood-borne cancer.

"The way that cancer affects people with Down syndrome is just so intriguing from both perspectives," said Dr. Jeffrey Toretsky, a pediatric oncologist at Georgetown University's Lombardi Comprehensive Cancer Center. "Why do they get more leukemias but fewer solid tumors?"

Ryeom and the other scientists embarked on a series of tests exploring the tumor part of the equation. Test after test, the evidence accumulated.

One experiment confirmed that people with Down syndrome have elevated levels of the gene, which is known by different names, including DSCR-1: Down syndrome candidate region-1.

In another test, mice were bred with three copies of the DSCR-1 gene - meant to mimic the three copies in humans with the syndrome - and then injected with cancer cells. Those mice wound up developing tumors that grew only half as fast and were half as large as in normal mice.

Finally, stem cell pioneer George Q. Daley of Children's Hospital harvested skin samples from adults with Down syndrome as well as from other people. Using genetic technology, the skin was transformed into human stem cells that, in turn, were injected into mice. The potent stem cells divided chaotically, spawning harmless tumors that proved to be ideal models for studying blood vessel development.

The result: The benign masses stemming from the Down syndrome stem cells showed almost no blood vessel formation, a stark comparison with robust vessel growth in the other tumors.

The findings led researchers to conclude that having the extra supply of DSCR-1 genes was a significant - although not complete - factor in preventing tumor blood vessel formation in people with Down syndrome. They also mined evidence that a second gene out of the 231 on chromosome 21 impedes vessel growth.

Researchers from Children's, as well as independent specialists, predicted that the discovery could guide development of drugs to mimic the effect of Down syndrome in patients stricken with cancer. But they went further, suggesting that one day, healthy adults might regularly take a pill to prevent the rogue blood vessels from forming and, thus, stop microscopic tumors from turning into something dangerous.

But any drug to prevent cancer would have to clear a far steeper safety hurdle than medications given to patients who already have life-threatening tumors.

"Cancer prevention strategies are really the holy grail, but they're tricky because you have to use an approach that is nontoxic and that people can be exposed to for years and years," said Dr. Crystal Mackall, chief of pediatric oncology at the National Cancer Institute.

The discovery emerges at a time when much of the cancer research world is obsessed with developing personalized treatments, rather than approaches to more broadly defeat the disease. To his last day, the charismatic Folkman subscribed to a vision of cancer treatment that could help the greatest number of patients. His work, scorned for years until being embraced in many corners, provided the blueprint for drugs such as Avastin, a medication shown to choke off the blood supply to tumors and slow vision loss in patients with leaky blood vessels in their eyes.

Folkman's death in January 2008 occurred as the Down syndrome researchers were about to begin tumor experiments in mice.

"He never got to see it come to fruition, which is really unfortunate," Ryeom, one of his scientific progeny, lamented. "But somehow, I just think he knows."

Stephen Smith can be reached at stsmith@globe.com.

© Copyright 2009 Globe Newspaper Company.