Saturday, August 28, 2004

New Understanding of Genetic Plasticity
An Illustation of a General Concept

Frederick W. Alt, Ph.D.Frederick W. Alt, Ph.D. along with Jayanta Chaudhuri and Chan Khoung, have published a paper  in Nature, entitled Replication protein A interacts with AID to promote deamination of somatic hypermutation targets.  A somewhat less abstruse version  can be found at the Howard Hughes Medical Institute website, along with additional information here.

The studies focus on B cells, specialized immune cells responsible for producing antibodies, and how an enzyme in those cells known as activation-induced cytidine deaminase (AID) triggers mutations of antibody gene segments to produce an assortment of antibody proteins. This process enables the immune system to produce antibodies that will recognize billions of different antigens – the fragments of foreign invaders that are used to call the immune system to arms.

The presence of an antigen on the surface of a B cell stimulates it to produce antibodies. An important step in this process is the activation of AID, which causes largely random mutations in the genes for the antibody segments that recognize antigens. These mutations occur about a million times more frequently than spontaneous mutations in other genes. In this process, known as somatic hypermutation, AID selectively “damages” the DNA strand, prompting the DNA repair system to create the mutations.

AID also triggers class switch recombination, a highly specific process that involves recombining gene segments that encode the part of the antibody molecule that direct it where to take its antigen cargo and how to dispose of it.

The Nature paper and the reports on the HHMI website go into detail about why this is important in the field of Immunology, mentioning that it could have implications in the understanding of the development, and the treatment, of lymphoma.

That is great, but it is not what drew the interest of The Corpus Callosum.

The article illustrates an important general concept in biology: all systems are dynamic. That is, no structure in a biological system can be modeled accurately as a static thing. In order to really understand something in biology, it is necessary to appreciate the fact that everything changes all the time. In introductory biology, we are taught that DNA is made up of a string of nucleotides, and that the sequence of the nucleotides is what carries the information needed to make proteins. That is only vaguely correct. It encourages one to think of DNA as being analogous to the printed letters on a page of text: static, unchanging. We are taught that mutations occur, but they are thought of as exceptional, accidental events.

Now, we learn that mutations are not always accidental. In fact, some cells have a mechanism that exists for the specific purpose of causing mutations. No only that, but when the system is activated, it produces mutations by the millions. The idea that mutations in such large numbers might actually be beneficial seems, at first glance, to be completely counterintuitive. That illustrates a second general principle: intuition is a tricky thing.