The diversity of the immune system’s antibodies depends on the three-dimensional structure of DNA.

Fred Alt has built a career making sense of the immune system—specifically, the diverse antibodies that fight off invading molecules, from viruses to cancer cells to pollen.

Imagine that the only road connecting two cities had rollercoaster-inspired loops. Cars and trucks attempting to make the journey would plummet off the highway. It would surely discourage direct traffic between the towns.

In the cell, where molecular machines constantly travel along strands of genetic material, such uninviting loops and curls are commonplace. They help keep proteins from accessing genes the cell doesn’t need at the time. Later, when the cell needs the genes to be activated, the dizzying roundabouts can be straightened out to support molecular traffic.

In the late 1970s, when HHMI investigator Fred Alt at Children’s Hospital Boston started studying the human immune system, he had no idea this higher-order structure of DNA even existed. Today, he’s found that the way DNA is packaged into three-dimensional structures is crucial to every immune process he’s looked at.

Alt studies how the immune system generates antibodies against any potential invader to the body—from a virus to a cancer cell or bit of pollen. When an antibody recognizes an invader, it signals the rest of the immune system to destroy it. This means millions of different antibodies are somehow encoded in the DNA of immune cells to recognize all types of invading molecules.

“It’s important for a cell to make only one type of antibody at a time,” says Alt. In immunology, that quality is called specificity. “But it’s also important that different cells make different antibodies.” This is diversity.

If the immune system had enough genes for every possible antibody the body might need, our genomes would be exponentially larger than they are. Instead, immune cells combine different bits of genes in different ways to make millions of unique combinations. Three gene segments—dubbed variable (or V, for short), diversity (D), and joining (J)—are the basis for these permutations.

In 1984, Alt discovered that immune cells always combine a D and J segment before adding a V. Cells early in their development, he found, contained partial antibody genes composed of only Ds and Js. When Alt grew those cells in the lab, the antibody genes added a V later in the cell’s development. He has since worked out some of the proteins responsible for combining these gene segments in different ways. And he’s pinpointed how the cell makes sure only one antibody is produced—by suppressing alternate antibody genes once a combination is successfully produced.

Photo: Jared Leeds

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