Please Pass the Salt

January

31

My thoughts on genetic medicine

Today is a landmark day for both the medical and scientific community: the FDA approved a drug designed specifically to treat and correct the effects of a genetic defect—a first in “genetic” medicine.  This drug, KALYDECO, was developed by the pharmaceutical company Vertex to correct the folding of the defective protein responsible for a specific genotype cystic fibrosis.  KALYDECO, a small molecule, helps the misfolded cystic fibrosis transmembrane conductor (CFTR) protein correct itself so that it can function properly. 

In 1989, during the height and fame of the Human Genome Project, the cystic fibrosis gene was discovered.  The discovery was expected to be followed by the development of gene therapy to correct this faulty gene and thus render cystic fibrosis cured and a thing of the past.  Years later, researchers have come to know that this gene codes for a specific membrane protein which controls the transport of chloride in and out of cells (cystic fibrosis transmembrane regulator, or CFTR), which helps to maintain the appropriate salinity (salt concentration) in the body and is of particular importance in the respiratory and digestive systems.  Because it doesn’t function properly in people with cystic fibrosis, they secrete abnormally thick mucus in their lungs, which is difficult for the lungs to naturally clear away.  The abnormally thick, sticky mucus stays in the lungs and becomes infected with bacteria, leading to a cascade of immune system responses that result in airway remodeling and ultimately progressively decreased lung function.

When I was a student in high school and college learning about genetics and trying to understand how they fit into my life with my disease, it became clear to me at some point that gene therapy had the fatal complication that if it “fixed” the gene in one cell, how would that propagate as that cell grew, divided and died?  And knowing that every single cell in my body has this genetic defect, it seemed like a daunting task to replace the bad gene with a perfect one in every single cell, especially owing to the fact that the longevity of the success would depend on whether the cells could reproduce with the new, improved gene in place of the old bad one.  I realize there have been remarkable advances in genetic therapy and genetic engineering (in fact, one of the medications I take is synthesized by genetically engineered hamster ovary cells), but from my reading and understanding, there is a significant hurdle to clear in order to get the same sort of engineering success from the petri dish into the living body.  Therefore, the momentary hope that the discovery of the CF gene brought the medical and CF community with regards to future gene therapy has never been something I’ve been counting on to succeed in my lifetime.

As a scientist, I have loved and enjoyed the process of the scientific method: performing experiments, interpreting results and planning the next step in the process for problem solving.  One thing I particularly experienced (as nearly anyone who has worked on a PhD in science/engineering/medicine will) was deciding what to do when your experiments don’t go the way you planned.  You have bad or unexpected results that do not seem to aid in solving the problem you intended.  There are two things you can do in this circumstance: 1) try approaching the problem from a different direction and 2) try to figure out what your results mean and where they will lead you next.  Often times it’s a combination of both and you gain new insight into why the first approach didn’t work and can then come up with an alternative approach.  I’m a firm believer that scientific discovery comes from unexpected results.

From a purely academic perspective, coming up with the idea to use a simple and small molecule to correct the problems created by the mutated gene rather than try to correct the gene itself is fascinating.  All of the research and experiments done to understand how the CFTR protein works, while not yet successful in leading to the development of a means to introduce a corrected gene, have given remarkable insight into the physiological cause of the disease.  That understanding has allowed scientists to look at the problem from a different direction: instead of preventing the problem from occurring (introducing a corrected gene), why not try to correct the primary mistake the gene creates?  On a cellular level, the defect is remarkably simple even though the resultant disease and symptoms are complicated and unpredictable. 

The beauty of it is that this scientific approach to the problem works.  There is a way to correct the misfolded CFTR protein that a specific genetic mutation codes for, which in essence will halt the disease progress and thereby can potentially “cure” the 4% of the CF population who posses this specific genetic miscoding. 

From a personal perspective, while this particular drug is not designed to treat my specific genetic mutation of CF, it gives me an incredible amount of hope and is rather awe-inspiring, in that it represents a triumph of science over an unfortunate, uncontrollable and eventually fatal random genetic error in the way 70,000 CF patients worldwide were made.  It is not my “cure” but its presence portends re-doubled research efforts to develop and test the next drug that WILL be my cure. 

It seems to represent the same excitement and hope as the discovery of penicillin in 1928: what bacteria it can treat, it treats well; it can’t treat everything, but its mere existence opened up the door to a whole new field of research aimed at finding other similar chemical compounds that have the same antibiotic effects on other bacteria.  What genetic mishap KALYDECO repairs, it repairs well; it can’t repair every genetic mishap that results in cystic fibrosis, but its mere existence opens up the door to a whole new field of research in cystic fibrosis and other diseases. 

This post has 3 notes and tag: # cystic fibrosis # KALYDECO # science # Vertex Pharmaceuticals .

January

19

A fun day at work

Today has been the most fun day at work in quite awhile. For my newer readers, I work at a multi-user analytical facility at a large research university. We have lots of fancy, expensive “science machines” (microscopes and spectrometers) that engineering and science students use (kind of like CSI, but not really).

Today’s highlights include:

-Some sales guys are visiting our facility to do a demo of a fancy microscope (optical profilometer) that can take topographic images (of pretty much anything) with angstrom resolution in the Z direction (vertical). I hope we buy this new science toy.

-The sales guys treated me to lunch at Chipotle

-My favorite service guy is here repairing another instrument

-An undergrad student I trained two summers ago who I haven’t seen since just stopped by my office to tell me hi, that she’s graduating, and all about her new job. Things like this make me really like my job.

-I neither have a headache nor feel exhausted nor want to hide under my desk and sleep for the first time in a week. I think maybe I had a mild cold/virus.

This post has 9 notes and tag: # science # metrology # microscope .