MIT Researchers Identify ‘Master Builder’ Gene : Science: The gene controls the body’s disease-fighting process. The discovery has no immediate medical application, but could lead to the development of drugs that would fine-tune the immune system.

Molecular biologists from the Massachusetts Institute of Technology report that they have isolated and identified the “master builder” gene that controls the disease-fighting process, marshaling its forces like a general preparing to repel an enemy invasion.

The discovery, reported in today’s Cell journal, should provide fundamental new insights into how the immune system functions, according to pathologist Michael Lieber of Stanford University. “I would think it would be one of the top 10 . . . discoveries in immunology,” Lieber said.

“It is a remarkable technical achievement, an extremely elegant piece of science,” added molecular immunologist Frederick Alt of Columbia University in New York City. “We now have in hand the tools to dissect the system that is involved in the assembly of antibody genes. We’ll make a tremendous amount of progress in the next year.”

The discovery of how this process is controlled has no immediate medical application, but the finding could eventually lead to the development of drugs that would fine-tune the immune system. Even further off, it might lead to ways to repair the ravages of the immune system caused by the AIDS virus.

Over a lifetime, a human encounters literally tens of thousands of different infectious bacteria, viruses, fungi and parasites. Most of the time, these encounters are benign because humans have evolved a remarkable immune mechanism that, at any given time, posts more than 100,000 unique sentries to identify the invaders and sound the warning call for their destruction.

Surprisingly, the body’s genetic repertoire does not have a set of genes that serve as blueprints for each of these sentries, called B cells. Instead, it has a small library of DNA (deoxyribonucleic acid) fragments that are constantly being chopped up, shuffled and recombined to produce millions of different B cells over the course of a lifetime.

Defects in the gene may be responsible for some of the genetic diseases that produce a non-functioning immune system, such as that suffered by David, the “bubble boy” in Houston who spent all of his short life in a plastic-enclosed, sterile environment.

Defects might also lead to the formation of tumors of the immune system.

Some biologists believe that a similar shuffling and recombining process may play a role in the differentiation of unspecialized cells in the early embryo into specialized cells in various organs, particularly in the brain and nervous and sensory systems. The gene that has been identified could be used as a probe to locate such genes in other systems.

Biologists have long puzzled over the riddle of how the body could generate the large number of individual antibody-secreting cells that are known to exist in the immune system. Immunologist Susumu Tonegawa of Japan solved that in the early 1980s by demonstrating that a small genetic library could be constantly reshuffled and recombined to produce the necessary number of antibodies--a feat for which he won the 1989 Nobel Prize for Medicine.

“Since then, we have learned surprisingly little” about how the body achieves this rearrangement, said molecular biologist David Baltimore of MIT’s Whitehead Institute for Biomedical Research, the leader of the team that isolated the gene. “This is the first step toward finding a chemical basis of diversity.”

Baltimore and two graduate students, David G. Schatz and Marjorie A. Oettinger, isolated the gene from human white blood cells. They were able to prove the gene’s function by inserting it into cultured skin cells, which--like all cells in the body other than immune cells--cannot normally carry out the shuffling and recombination process.

After the gene was inserted, the skin cells were able to do so, Oettinger said in a telephone interview.

The researchers still do not know precisely how the gene functions, however. In fact, there are two possibilities.

One is that the gene codes for an enzyme called recombinase. That enzyme, Lieber said, is a “molecular surgeon” that actually carries out the cutting and recombining process.

Alternatively, the gene could operate at the genetic level, orchestrating the entire recombination process by turning on and off the genes for recombinase and other components of the system.

For a variety of reasons, the MIT group believes that the gene is the blueprint for the recombinase, Oettinger said. But either way, she said, “It is going to teach us a lot more about the basic science of the immune system.”