Mechanisms Versus Causes in Biology and Medicine - Mechanism and Causality in Biology and Economics - page 30

stage in the disease with different targets than the CFTR protein biosynthesis
mechanism (Chmiel and Davis 2003 ).
This hypothesized mechanism of overexpression of the immune response to
inflammation led to the unexpected prediction that anti-inflammatory drugs would
be beneficial to CF patients. Without this hypothesis, one would have expected that
anti-inflammatory drugs, such as ibuprofen, would have deleterious effects for
lungs susceptible to infections. The normal inflammatory response, which recruits
neutrophils to the site of an infection, is beneficial in the fight against bacteria.
However, because the hypothesized mechanism suggested overexpression of this
response, the drug therapy to reduce the response was subjected to a clinical trial,
with some success (Konstan et al. 1995 ).
So, this case shows the many different ways the puzzling phenomenon can be
identified and consequently the many different mechanisms that provide candidate
“causes” for that chosen phenomenon. If the phenomenon to be explained is the
synthesis of the normal CFTR protein, then the mechanism for that is well under-
stood. If the question is the following—“what is the nature of the failure in that gene
that leads to cystic fibrosis disease?”—then the answer is that there are many
mutations that disrupt that mechanism in different ways (as we discussed, different
classes of mutants disrupt the normal mechanism at different stages). If we focus on
the most common mutant found in those with cystic fibrosis in the USA, the Delta F
508 mutation, then the puzzling phenomenon is how does the CFTR protein misfold
and get degraded (or not). Although some of the details of the degradation mecha-
nism are still black boxes, nonetheless, we know that the outcome is that some
misfolded proteins are found in the cells. Hence, enough of the mechanism is
understood to direct empirical or rational drug discovery efforts, which may find
a way to correct the misfolding and transport the protein to the cell membrane. The
goal is to elicit sufficient amounts of chloride ion transport to restore some of the
normal function and alleviate some of the disease symptoms.
However, if we want to know the mechanism by which this mutant leads to lung
disease and death in CF patients, then there are still many black boxes to be filled.
Competing hypotheses have to be evaluated about crucial stages of different
mechanisms. To decrease death due to bacterial infections, it may be possible to
direct therapeutic effects to the regulation of overexpression of neutrophils rather
than correcting the CFTR gene itself. A different mechanism, coming later in the
progression of the disease, becomes the target mechanism for controlling one
disease symptom.
This case shows that the mechanistic perspective adds much more detail than a
simple claim that a mutated gene causes the disease cystic fibrosis. That vague
claim has been eliminated in favor of a rich description of the many mechanisms
involved. One would have thought that for a disease due primarily to a single gene
defect, we could say that the mutation in the gene causes the disease and the way to
fix it is to apply gene therapy to deliver a functional, non-mutated gene. Sadly such
a simple fix did not work. This case shows the importance of knowing the different
stages of the normal mechanism and the specific ways in which it breaks and even
identifying different mechanisms that come into play as the disease progresses. All
these aid drug discovery.