Jim Lupski was luckier than his older brother, who even before his 5th birthday lost the ability to run and walked only with exceptional pain.

Doctors suspected muscular dystrophy. They were wrong.

Lupski's symptoms of the same disease didn't appear until he turned 15, when doctors realized it must be a genetic nerve disorder. After a diagnosis of the relatively rare Charcot-Marie Tooth disease, Lupski endured 10 surgeries, spending most of his sophomore and junior years on Long Island in a wheelchair at home. .

During these sedentary days, Lupski battled his disease the only way he could, immersed into the nascent field of genetics to understand how he and his brother could acquire such an illness from two healthy parents.

Four decades on as a seasoned researcher at Baylor College of Medicine, Lupski, 53, has finally traced the faint genetic filaments of his disease to understand its origin.

What is perhaps most remarkable about the answer is how it was found: For the first time, geneticists sequenced a person's entire genome, Lupski's, to identify the genetic cause of a disease.

“This is an immense step forward for personalized medicine,” said Richard Gibbs, director of Baylor's Human Genome Sequencing Center.

That is, it heralds the coming day when many diseases will be identifiable by a less than $1,000 genome sequence, and then treated with a tailor-made drug regimen to match the specific illness.

The New England Journal of Medicine published the Lupski paper online Wednesday, along with an editorial by Dr. Richard Lifton, a Yale University geneticist who wrote that the study provides a striking “glimpse of the future” of medicine.

That's not what Lupski set out to do. He just wanted to understand why the muscles in his legs and feet were wasting away.

During college at New York University, he wrote to DNA pioneer James Watson and spent two summers working for the co-discoverer of DNA's structure at Cold Spring Harbor Laboratory in New York.

Lupski would earn a research and a medical degree because he wanted to understand the cause of his family's disease, which now affected four of his eight siblings, and help others affected by it.

After graduating, he found Baylor, with its ties to Texas Children's Hospital and its emerging genetics program, a perfect fit. He arrived in 1983.

A discovery in 1991

His first major breakthrough with Charcot-Marie Tooth disease came eight years later when he and colleagues found the genetic cause of the most common variant of the disease. The issue was not a tiny mutation of gene, Lupski found, but rather a duplication of a gene, like a repeated word in a sentence.

“It was a completely new concept,” Lupski said .

Today, scientists attribute duplicated genes, or copy-number variations, to a host of diseases.

With the 1991 discovery, scientists had a way to identify the genetic cause of 70 percent of Charcot-Marie Tooth patients, but Lupski's family wasn't among them.

“It was gratifying to find the genes and have new insights into the disease,” he said. “But yeah, it was disappointing that we couldn't find the gene important in my family.”

Since then scientists have identified nearly 40 regions in the genome where mutations or copy-number variations can cause Charcot-Marie Tooth disease. About 10 have available tests to screen for the disease. Again, none matched Lupski's disease.

Amazing variations

Three years ago, he survived cancer. The radiation therapy played havoc with his nerves. He wondered whether he might ever trace the genetic roots of his disease.

So, he turned to Gibbs, a colleague, who played a major role in the project to sequence the first human genome, and has since sequenced the genomes of Watson, Desmond Tutu and a few others. Would Gibbs sequence his genome to find an answer?

Geneticists have found the vast majority of genes that contribute to ailments by studying the genetic makeup of a large group with a particular disease, and a group of people without it, and looking at the differences.

Yet as Gibbs and others have sequenced the full genomes of individuals, they have found an amazing amount of variation, an average of about 3.5 million differences between two individuals' genomes.

Out of these millions of differences between Lupski and the other genomes, would it be possible for scientists to identify the one or two genetic changes that caused the variation of Charcot-Marie Tooth disease in Lupski's family?

That's just what they were able to do, finding two mutations on a single gene associated with Charcot-Marie Tooth disease. Lupski's father carried one of the mutations, and his mother the other.

The four children who got copies of both mutations from their parents got the disease.

“It's tremendously gratifying to find the answer after all of this time,” Lupski said.

But does it mean anything clinically?

In the history of Charcot-Marie Tooth disease, and many other ailments, doctors have treated only symptoms, such as the surgery Lupski had to fuse his ankle a decade ago. Now there's the promise of treating the cause.

“At one point in the history of medicine, if the doctor listened to your lungs and heard a certain sound, you had pneumonia,” Lupski said. “That's all you needed to know because there was nothing you could do about it.

“But now we need to know whether it's bacterial pneumonia, viral pneumonia, fungal pneumonia, etc. because our therapies are much more directed at the cause.”

It's an analogy that is beginning to apply to the various forms of Charcot-Marie Tooth disease. For example, a drug to treat the disease's most common form, the cause of which Lupski identified in 1993, is now advancing through clinical trials.