Boy rewrites his genetic legacy

Published July 2, 1996|Updated Sept. 16, 2005

Without sophisticated medical intervention, the faulty genes Jordan Houghton inherited should have killed him by age 4 or so. They already had killed a brother, Beau, at 18 months.

But marveling scientists report that Jordan managed to heal himself, returning a flawed gene to normal.

Today, the Stanton, Mich., youth is a healthy 13-year-old who builds tree houses, earns A's and B's and plays saxophone in the school band.

Somehow, at some unknown time, Jordan's body rewrote his genetic legacy and stopped his disease, correcting a tiny but crucial typographical error in one stretch of DNA. The fix may have occurred first in just one cell of his body. That would be akin to taking a desk piled high with multiple stacks of paper, all photocopies of a single, thousand-word treatise, and fixing the word "knit" to "knot" on just one page.

"This little boy, instead of dying, got better," said Dr. Rochelle Hirschhorn of the New York University Medical School. She led a team of researchers who describe their investigation of Jordan's remarkable case in the July issue of the journal Nature Genetics.

This is the best-documented example of a very rare event, said a gene expert familiar with the report, Dr. Hagop Youssoufian of Brigham and Women's Hospital and Harvard Medical School. He said he thinks fewer than a dozen examples of such natural gene fixes have been reported.

Jordan was born with ADA deficiency, a rare condition that occurs about once in 1-million births. Because of the disease, cells have defective versions of a gene that normally directs them to make ADA enzyme, a "housekeeping" protein that eliminates substances that can poison immune system cells.

With a defective gene, a cell makes little or no ADA enzyme. That devastates the immune system and leaves the patient vulnerable to recurring infections.

Most children with ADA deficiency can be treated successfully with bone marrow transplants or regular injections of the missing enzyme.

As an infant, Jordan was plagued with recurring pneumonia and diarrhea, boils and sinus infections, and he grew slowly. He was 2 when he first visited Dr. Lawrence Kurlandsky of Grand Rapids, Mich., for pneumonia; lab tests showed major trouble in the immune system.

Looking at the lab results, "You think, "Oh, my gosh, he ought to be overwhelmed with infections,' " Kurlandsky said. Yet his infections responded to common medication, and Jordan kept coming back.

Jordan's brother Beau, on the other hand, had shared many of the same ailments but did not respond to medications. He succumbed to pneumonia four years before Jordan was born.

Jordan never needed a marrow transplant or enzyme injections, Kurlandsky said. When Jordan was about 5, the physician said, "he all of a sudden started doing quite well with very little help from me."

And since he was 8, his health has been basically normal.

"We haven't had any serious problems for the last four, five years," said Jordan's mother, Sue Ellen Houghton. "He hasn't even had a cold the last few years."

In their report, Hirschhorn, Kurlandsky and co-workers present evidence that a defective gene was repaired naturally, although how the boy's body accomplished that remains a mystery.

Everybody inherits two copies of the ADA enzyme gene, one from each parent. The disease occurs only when both copies are defective.

The Nature Genetics report shows that Sue Ellen and David Houghton both have one defective copy of that gene, although their flaws are different, and they passed them along to Jordan.

In some of the boy's blood cells, one gene copy has the mother's defect and the other has the father's flaw, showing clear inheritance of the potentially lethal double dose of defects.

But others of Jordan's blood cells are different. They still show the father's flawed copy. But the gene copy from his mother is normal; the tiny but devastating defect is gone, the gene is repaired. Out of more than a thousand crucial chemical links in the ADA enzyme copy, the single incorrect link has been replaced by precisely the right one.

The initial fix may have happened in a single blood cell. But that cell, with one normal copy of the gene, would alone have been able to make more ADA enzyme than multiple cells with only defective copies. That would give the cell a growth advantage, allowing it to flourish and produce offspring that inherited the same advantage, allowing them to flourish, too.

The result: a burgeoning population of genetically repaired cells that could make enough ADA enzyme to clear out potential toxins, thus strengthening the immune system and easing Jordan's illness.

Nobody knows when the fix happened, not even whether it occurred before or after birth.

Nor is it clear whether the repaired cells will be able to suppress the disease for the rest of Jordan's life, Hirschhorn said.

But "so far he's doing shockingly well," said his doctor, Kurlandsky. "In fact, he probably doesn't even need me."