Mechanisms Versus Causes in Biology and Medicine - Mechanism and Causality in Biology and Economics - page 28

4.3 Mechanisms Related to Cystic Fibrosis
So, there is a tidy story that we can now tell about the normal gene and the synthesis
of the normal CFTR protein and about how different mutations produce different
defects. Consider the mechanism for producing the protein with the Delta F 508
mutation. Each stage of the mechanism becomes a potential target for therapy. As
Susan Lindee has discussed, the early hope was for gene therapy to replace the
defective gene. The many problems with this approach include finding an appropri-
ate vector for delivering the large gene, getting the gene into the appropriate cells
(even in the lung cells which are more accessible than those in other organs), getting
the gene to a safe location (either chromosomal or an extrachromosomal plasmid)
so as not to disrupt other mechanisms, getting sufficient amounts of genes into the
cells, preventing the immune system from rejecting any foreign matter used to take
the gene into the cell, and getting the genes to respond to cellular regulatory signals
to turn on the gene but not to overproduce the protein (Curlee and Sorscher 2003 ).
These problems have yet to be solved; the prospects for successful gene therapy
look dim in the case of CF (Lindee and Mueller 2011 ).
So, consider the next module of the mechanism, the one after the gene itself, as a
target: the messenger RNA. The CFTR gene contains not only the coding sequences
that eventually direct the ordering of amino acids during protein synthesis but also
spacer segments, called introns. A cell organelle, called a “spliceosome,” processes
the pre-mRNA to produce the mRNA; the spliceosome accomplishes this by
snipping out the introns and binding the remaining coding segments together into
the final messenger RNA. Researches have succeeded in inserting a minigene into
the DNA of human lung tissue grafted onto a mouse. The minigene has the correct
coding segment rather than the Delta F 508 three-base mutation. The gene is
expressed at the same time as the CFTR gene, thereby overcoming one of the
barriers to gene therapy. Then the splicing machinery is induced to put the correct
segment into the processed messenger RNA rather than the mutant segment. Some
success in the mouse system makes this look promising. However, it is still a long
way from human clinical trials (Liu et al. 2002 , 2005 ; discussed in Thomson 2002 ).
Currently, a primary area for targeted drug therapies is the next stage of the
mechanism: the synthesis of the misfolded protein. For the Delta F 508 mutant, the
three missing bases in the gene result in one amino acid missing from the protein,
which then misfolds. Although some of the protein degrades, some of the misfolded
protein remains in the cells. Therapy can be directed to finding drugs that aid in
rescuing the undegraded misfolded protein so that it refolds and inserts into the
cell membrane and functions (albeit at a reduced level) to transport chloride ions.
A robotic process has screened millions of compounds for their effects on the
misfolded protein and some promising drug candidates have been found. One is
curcumin, a major constituent of the spice turmeric, which has shown promising
effects in vitro and in mice models (Rowe et al. 2005 , p. 1999).
In contrast to this random screening, rational drug therapy is also being explored.
Medical researchers are using a more detailed understanding of the role of