Tuesday, May 10, 2005

Chimera

A recent article (subscription required) in the NY Times Science section discusses the role of interspecies chimeras in biomedical research. They point out the chimeric organisms are nothing new:
“Biologists have been generating chimeras for years, though until now of a generally bland variety. If you mix the embryonic cells of a black mouse and a white mouse, you get a patchwork mouse, in which the cells from the two donors contribute to the coat and to tissues throughout the body. Cells can also be added at a later stage to specific organs; people who carry pig heart valves are, at least technically, chimeric.”
Regardless of the minimal ethical controversy amongst biologists, new research using other animals (e.g., pigs) to harvest human organs derived from progenitor cells has the potential to "gross out" most Americans. In essence, it's analogous to watching a horror film with a mad scientist manipulating the natural order for some (often undefined) egomaniacal purpose. According to the article,
“From the biologists' point of view, animals made to grow human tissues do not really raise novel issues because they can be categorized as animals with added human parts. Biologists are more concerned about animals in which human cells have become seeded throughout the system.”
I am neither a developmental biologist, knowledgeable in biomedical ethics, nor too concerned with the entire stem cell debate (which I think falls into this debate somewhere). What I am interested is molecular biology, genetics, and evolution, where there is a great history of chimeric forms. I'll discuss some of the ones I find most interesting below.

Chimeric genes play an integral role in molecular biological research. One such example is the GAL4-UAS system. By combining the upstream activation site (UAS) for the yeast gene GAL4 with your gene of interest, you can cause your gene to be activated in the presence of GAL4. These chimera aren’t structurally different (i.e., it is still the same protein), but instead of the normal regulatory elements associated with the gene, it now has the yeast UAS. A researcher can control where the GAL4 gene is expressed by creating a chimera made up of the GAL4 gene and a regulatory element for a certain tissue. Wherever GAL4 is expressed, your gene of interest will be expressed because it has been fused to the UAS.

Researchers often use fusion proteins to study the location of a particular protein in an organism or cell. These fusion proteins are a chimera of the coding sequence of a gene of interest and some label (often times a fluorescent protein such as green fluorescent protein, a.k.a. GFP). Studies of this sort can be used to view where a gene is expressed, how an organ develops, or how some subcellular machinery functions. I won’t go any further into this topic as it’s beyond my area of expertise, but hopefully I’ve shown the utility of molecular chimeras in biological research.

What I find most interesting are naturally occurring chimeras. The NY Times article makes the point that chimera violate natural laws. We are quickly realizing that molecular chimeras, however, are common in nature. The easiest of these to comprehend is interspecies hybridization (whole genome chimeras). Hybridization has the potential to induce speciation, and these species can be thought of as a chimera of the two parent species (yes, I do realize that I’m stretching the concept of chimera a bit here).

Better examples of natural occurring chimera resemble fusion genes used in molecular biology laboratories. One such gene (jingwei) has been studied by Manyuan Long for over a decade. Long and his colleagues have shown that a transcript of the gene alcohol dehydrogenase (Adh) inserted into the middle of another gene (yellow emperor) in the Drosophila melanogaster genome. The insertion interrupted the normal functioning of yellow emperor – an event that would oftentimes be under strong negative selection. It is expected that the insertion event would be selected against, but in this instance there was strong positive selection for this chimeric gene. In case you are curious, the naming of these genes (jingwei and yellow emperor) comes from Chinese mythology.

Other naturally occurring chimeric genes resemble the GAL4-UAS system – a complete open reading frame (i.e., protein coding sequence) fused to a new regulatory region. This is usually what happens when a retrotransposed gene becomes a functional gene. As we begin to accumulate more genome sequences, comparative techniques should enable us to find more example of naturally occurring molecular chimeras. Another Adh fusion gene has recently been found, and many more Drosophila fusion genes may be identified with the wealth of genomic data. I have identified a couple of partially duplicate genes in the Drosophila genome that I study that may form functional transcripts with the genes they inserted next to. I hope to characterize these further in order to further understand the role of chimera in molecular evolution.

1 Comments:

At 4:27 PM, Anonymous courtney hodges said...

We should also not forget the continuing importance of chimeras and hybridomas in pharmaceutical biotechnology. Chimeric human/mouse hybridomas have been used to express first- and second-generation monoclonal antibodies for a variety of therapeutic purposes:

- Abciximab, approved for prevention of clotting during surgery;
- Rituximab, approved for treatment of non-Hodgkin's lymphoma;
- Basiliximab, approved for prevention of kidney rejection after transplant;
- Infliximab, approved for Crohn's disease and the treatment of rheumatoid arthritis;
- Trastuzumab (Herceptin), approved for the treatment of metastatic breat cancer.

If there's such an ethical dilemma about using chimeric animals, shouldn't we also be discussing the benefits of this type of work? This is one area where public education about the benefits of modern biology would be extremely helpful.

 

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