Mechanisms Versus Causes in Biology and Medicine - Mechanism and Causality in Biology and Economics - page 29

additional molecules to try to correct the defect. These additional molecules, called
chaperones, aid the CFTR protein to fold properly (Wang et al. 2006 ). The
discovery of the role played by such additional molecules that interact with
CFTR (produced by additional genes, called “modifier” genes) may explain a
puzzling phenomenon about the relation between genotype and phenotype. It is
puzzling why patients with the same two Delta F508 mutations can still vary in the
severity of symptoms of the disease. One hypothesis is that this difference is due to
different modifier genes in their DNA. Although cystic fibrosis seemed to be an
ideal case of a disease caused by a mutation in a single gene, we can no longer hold
such an overly simple view. The mechanism by which modifier genes work
becomes important also.
Thus, we see the importance of the way the puzzling phenomenon is
characterized in order to focus attention on the relevant aspect of the mechanism.
When the puzzling phenomenon is the synthesis of the normal CFTR protein, that
mechanism is fairly well understood. But when the puzzling phenomenon is why
the Delta F 508 mutant protein fails to function properly, aspects of the mechanism
by which the mutant form of the protein is synthesized and misfolded and degraded
still have black boxes. Nonetheless, enough is known about that module of the
mechanism to guide drug discovery efforts to find drugs to aid with refolding the
misfolded protein.
However, when the puzzling phenomenon is a broader one, namely, how the
mutant in the CFTR gene produces the symptoms of cystic fibrosis disease in the
myriad organs that it affects, many of the details of these mechanisms are unknown.
When what is taken to be puzzling is much later in the progress of the disease, even
more black boxes remain. What are the stages of the mechanism leading to the thick
airway mucus in the lungs that result in the fact that, as cystic fibrosis patients age,
they become more susceptible to particular strains of bacteria that are more resistant
to treatment? Various hypotheses as to how to fill this black box abound. As a recent
review article said: “So far, a unifying mechanism responsible for the vast clinical
expression of the disease in the CF airway has not been identified” (Chmiel and
Davis 2003 , p. 173).
There are even competing hypotheses, which may not be mutually exclusive,
about why the airway mucus is thick and particularly susceptible to bacterial
infections. Several hypotheses depend on the effects of malfunctioning chloride
transport, leading to an imbalance of salt homeostasis or abnormal water absorption
producing thicker mucus (Widdicombe 2003 ). However, new evidence points to a
malfunctioning immune response. Neutrophils, which are a type of white blood
cell, are recruited to fight bacteria. CF patients also have defective regulation of
neutrophils, leading to an overabundance of them. The mechanism for this
malfunctioning regulation of neutrophils is not well understood, although some of
the entities and their activities have been identified (Gu et al. 2009 ). As neutrophils
break down, the debris, especially their DNA, accumulates in thick mucus that is a
site for colonization preferred by certain forms of bacteria. So, if the phenomenon
that the physician wishes to alter is the overgrowth of specific strains of bacteria,
then the therapeutic effects may be directed to neutrophil regulation, a much later