WORK REVEALS MANY FACES OF IMMUNE SYSTEM

Author: By Richard Saltus, Globe Staff

Date: Tuesday, October 13, 1987
Page: 10
Section: NATIONAL/FOREIGN

But human survival testifies to the evolutionary cleverness of the immune system.

As Susumu Tonegawa showed with an elegant experiment in 1976, the immune defenses can generate an almost limitless number of custom-made weapons to fight an equally wide range of biological and chemical enemies.

That milestone scientific paper, published when he was at the Basel Institute of Immunology, opened a new understanding of immunity. And it also forced scientists to accept something that previously was akin to heresy: the concept that the collection of genes that a person inherits is not necessarily a fixed endowment.

At Massachusetts Institute of Technology where he works, Tonegawa said yesterday that genes can rearrange themselves and change to meet a challenge -- in this case, to generate the amazing diversity of biological weapons for fighting disease.

"What we inherit is not finished genes," Tonegawa said at a press conference. "We inherit pieces of genes, and those pieces assemble in many different ways."

When Tonegawa reported his decisive findings, recalled Richard O. Hynes, professor of biology at MIT, "this experiment changed the entire way you teach the subject of immunology."

At a time when manipulating genes was much more difficult than now, "It was a radical experiment, one that made you say, 'My God, that's the way it is!' "

The announcement yesterday of Tonegawa's receipt of the Nobel Prize in Physiology or Medicine marked the third year recently in which the prize has involved research in immunology. The others were 1980 and 1984.

The awards reflect a growing understanding of the workings and the importance of the immune system, which plays a role in everything from bacterial infections to AIDS and cancer to organ transplants.

Tonegawa said his work does not directly apply to acquired immune deficiency syndrome, but could answer basic questions about the immune system that eventually will be helpful in fighting many diseases.

Immunity results from the complex interplay of different types of white blood cells and proteins circulating in the blood and tissues. Collectively, they resemble a country's armed forces with different branches, a defense network that goes into action when organisms or substances recognized as foreign enter the body.

Two principal types of cells specialize in defending against viruses and bacteria: they are called T-cells and B-cells. B-cells act like biological factories, churning out proteins called antibodies. The antibodies are so specific that for every distinct type of invader, there is a single type of antibody that seeks out the foreign molecule, sticks to it and signals other defensive units to destroy it.

But most proteins in the body are made according to chemical blueprints contained in a corresponding gene -- the smallest unit of inherited information. Human cells contain an estimated 50,000 to 100,000 genes.

How, then, could enough genes exist for each of the millions or possibly billions of antibodies needed to counter all conceivable enemies?

Before Tonegawa's work, some scientists argued that each person must be born with genes for the entire range of antibodies, while others said the body must somehow combine a small number of genes to yield the necessary number of antibodies. But such a mechanism was unknown.

Tonegawa devised an experiment to find out whether genes in immune cells were indeed rearranging themselves. If that were the case, it would explain how a small amount of basic genetic information could produce a great number of antibodies. By analogy, it takes only the numbers 0 through 9, shuffled in many ways, to generate telephone numbers for a huge population.

Tonegawa and Nobumichi Hozumi described in a 1976 paper how they compared immune cells from embryonic and mature mice, and found that the antibody genes in the embryonic mice were far apart. In the older mice, the genes were closer together, showing that they had been rearranged.

Later, Tonegawa and others found that mouse antibody genes contain three types of fragments -- about 100 of one type, 20 of another, and four of the third. By shuffling these and other elements in various combinations, the immune system can generate millions or even billions of different antibodies, said Tonegawa.

In recent years, Tonegawa and others have made discoveries showing that a similar mechanism allows T-cells -- the other main branch of the system -- to recognize an immense number of foreign invaders.

Ultimately, said Tonegawa, greater understanding should allow scientists to manipulate the immune system, fine tuning it to fight diseases more effectively, or turning it off when immunity goes awry, such as rejecting transplanted organs or damaging the body's own tissues.

Tonegawa, along with LeRoy Hood of the California Institute of Technology and Philip Leder of Harvard University, received the prestigious Lasker Award in medical research last month for immunology advances.

Tonegawa yesterday said he was surprised that he alone received the Nobel. Hynes of MIT said that in his view, it "could have gone either way."

SALTUS;10/12 NKELLY;10/14,15:17 SCIENC13