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James A. Shapiro

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Your Life Depends on Immune Cells Doing the 'Impossible': Purposeful, Targeted DNA Engineering (Part 2)

Posted: 04/ 3/2012 1:36 pm

Your immune system protects you with a set of remarkable molecules called "antibodies" (described in a YouTube lecture and on Wikipedia). Antibodies can recognize an infinite range of unknown invaders (e.g., viruses, bacteria, parasites, toxins) and tag them for destruction by other components of the immune system.

A prior blog explained how immune cells use targeted but flexible natural genetic engineering and rapid evolution to generate the immense diversity of antibodies needed to deal with unpredictable invaders. This posting will discuss how further targeted natural genetic engineering refines antibody specificity and directs antibodies to the right place in your body to deal with each infection. (An outline of this process on YouTube is also available, but note that the lecturer starts going off track at 7:45 and mistakes RNA splicing for the DNA changes described below.)

Before I explain more about what immune cells can do purposefully to their DNA, it is useful to remember that targeted DNA changes have been declared impossible by conventional evolutionary theory, which treats genetic change as accidental rather than functional. For instance, Jerry Coyne criticized another of my recent blogs on evolutionary theory with the following comment:

Mutational change occurs by accident, or as a byproduct of something else (like a gene being accidentally duplicated, or the ingestion of DNA from another species), but those changes occur whether or not they'd be "good" (i.e., increase the reproductive output of) individuals in the species that has mutated.

We will return to the importance of this philosophical difference later in the blog.

Once an immune cell producing an antibody of defined specificity has encountered and bound a particular antigen, it becomes "activated" and proliferates so that production of the antigen-specific antibody increases.

The antibody molecule has two overall parts: the "variable" (V) region, which differs for each invader, and the "constant" (C) region, which is the same in antibodies for many different invaders. Both parts of the molecule participate in the immune response. The V region binds to the invader, and the C region interacts with tissues, and other components of the immune response. To preserve this functional connection, the DNA changes that generate or modify coding sequences for antibodies have to be precisely targeted.

One set of changes, called "somatic hypermutation," targets DNA that encodes the V region of each antibody chain in activated immune cells. This process utilizes a variety of DNA modification tools adapted from proofreading and repair functions. Somatic hypermutation introduces multiple localized DNA mutations that specifically modify the antigen-binding properties of mutant antibodies; those with tighter (hence more effective) binding are amplified (Goodman, Scharff et al. 2007). DNA that encodes the C region is not detectably altered. Improving the binding specificity of antibodies during the immune response is called "affinity maturation."

The C region of the antibody is important 1) for distribution of antibodies throughout the various body tissues, and 2) for interactions with the different cells and molecules of the immune response. The initial IgM antibody has a Cμ constant region on its heavy chain and remains attached to the producing immune cell surface. From this position, it can signal the cell to proliferate when an antigen is bound. That is key to the immune system's rapid evolution process.

Other classes of antibody have different C regions and go to different places in the body. For example, IgG antibodies have Cγ heavy chain regions and circulate in the bloodstream (the "gamma-globulins"), where they interact with macrophages and the complement system, both of which destroy IgG-bound invaders. In contrast, IgA antibodies have Cα heavy chain regions and are targeted for secretion on mucosal surfaces that come in contact with foreign matter, like food and its digestion products.

How do the C regions switch? The answer is a specific kind of natural genetic engineering on the DNA encoding the heavy chains. The process is called "class switch recombination" (CSR). It involves targeting double-strand DNA breaks to special "switch" (S) signals upstream of different exons encoding alternative C regions. When a broken Sμ signal and a broken Sγ signal are joined, the fused sequence now encodes an IgG rather than an IgM heavy chain. Here's what the DNA changes look like schematically:

VDJ-Sμ-Cμ--(other S-C regions)--Sγ-Cγ → VDJ- {DNA BREAKS} -Cγ → VDJ-Sμ/Sγ-Cγ

Similarly, joining broken Sμ and Sα signals generates a sequence encoding an IgA heavy chain:

VDJ-Sμ-Cμ--(other S-C regions)--Sα-Cα → VDJ- {DNA BREAKS} -Cα → VDJ-Sμ/Sα-Cα

DNA breakage is controlled by transcription across each S signal. Sμ is transcribed in all cases because the activated antibody-producing cell produces IgM. Each of the other S signals has its own control sites; transcription is triggered by a distinct set of immune system signaling molecules. Apparently, immune cells responding to a bloodstream infection will signal Sγ transcription and switching to IgG, while immune cells responding to a mucosal surface infection will signal Sα transcription and switching to IgA.

Three remarkable things about somatic hypermutation and CSR are explicitly excluded from the prevailing philosophy of genetic change. First, they are adaptive and purposeful genome changes. Second, they are functionally targeted. Third, for CSR, targeting involves intercellular signals that depend on how other cells in the immune system perceive a particular infection.

If immune cells can do all the above, is there any scientific reason we would assume that other cells cannot do the same? Coupling DNA restructuring to transcription is of major significance. All cells can target transcription to functionally relevant sites in the genome. Given that the immune system is how evolution evolved rapid protein evolution, should we not look to it for clues about basic evolutionary processes?

The burden of explaining what other cells lack that lymphocytes possess lays with those who wish to adopt the position that the immune response is unique and does not reflect a more general capacity to target genome change. Evolution has obviously refined antibody-producing cells for their immune system functions. But do immune cells have unique capacities for natural genetic engineering missing in other cells? If the answer is no, as I believe, then we need to incorporate adaptive genome restructuring into our most fundamental thinking about biology.