PONDERING

Near Tofino, with Richard and Barbara Levin

I ponder a lot.  My cranky joints, depleted energy level, and oversized gut prevent me from doing much hiking, and whenever I go to the paleontology lab people ask me questions about geology, a disgraceful fraction of which I can’t answer.  This being the case I mostly stay home and read – which makes me sleepy – or try to decipher Internet articles about cancer – which makes me feel inadequate.  Thus I spend more time than is healthy, sitting on my patio watching birds – and pondering.  Here is what I have been pondering lately.

So lightning-fast, reasonably cheap genome sequencing, together with genome-wide association studies* enable us to detect the mutations (and there are many) responsible for cancer, and incredibly sophisticated (and expensive) laboratory experiments increasingly give insight on how these mutations actually work.   I am sure all this brings shivers of joy to theoretical cancer biologists, and Nobel money to a lucky few.  It gives these people something to talk about at conferences in Maui, or Santa Fe.  Great.  But how does it translate into actually curing cancer?  That’s what is plaguing me lately.  Some practical applications I see, but only a few.

Let’s take an example from ovarian cancer: the BRCA genes.  As you know, these are “damage-repair” genes; they fix damaged DNA.  Without functional BRCA, damaged – mutated – genes may cause cancer.  Obviously it is useful to know if you are BRCA-positive – it motivates you to form a close attachment to a competent oncologist, maximizing the probability that any tumor you might develop will be caught early and excised.  But can you “fix” the broken BRCA gene itself?  As far as I can see, no. 

Genes, as you are aware, are stretches of DNA that carry a molecular code which, properly processed, results in a protein.  Proteins, in turn, perform many tasks, one of which is to act as a messenger; that is, to activate a series of molecular transformations that result in something; for instance, cause the cell to divide.  That is what the ras gene does; it activates a pathway that causes cell division; ras is a “proto oncogene”.  When mutated it is in effect a jammed accelerator – it causes uncontrolled growth; cancer.  How to stop it?  If you could spot the initial mutation and acted quickly enough you might use CRISPR** technology to cut out the defective gene and replace it with a functional version – but, of course, that’s certainly impossible today, and probably always will be.  Maybe knowing about the malfunctioning ras gene will enable us to develop a drug that will counteract its ill effects, but such a drug probably would operate on every cell in the body, not just the cancer cells, or so it seems to me, possibly with ugly consequences.  So, a conundrum.  Nanotechnology involving delivering the drug directly to the tumor using tiny spheres may be the answer here***.

This is getting pretty long but I will continue.  You’ve probably quit reading already, anyway.

Offhand I can see one direct application of all this genetic knowledge.  It might be possible to “edit out” heritable mutations such as BRCA, using CRISPR technology on germ cells.  Easier said than done, clearly, but possible.  Unfortunately there are a truckload of such mutations****, and more are tossed on the truck every few days.  So, I will ponder on.  The hummingbirds are going nuts outside. 

*http://ljb-quiltcutie.blogspot.com/2016/02/zinc-fingers-and-progress.html

**http://ljb-quiltcutie.blogspot.com/2015/11/crispr-another-mystery-of-life.html

*** http://ljb-quiltcutie.blogspot.com/2013/11/nano-bombs-and-matryoshka-dolls.html

**** http://ljb-quiltcutie.blogspot.com/2013/08/tcga-youll-have-to-read-it-to-find-out.html