NOT OC: ANOTHER UNUSUAL MOUSE

I have no idea what's going on here.

My last blog entry introduced the concept of “cancer stem cells”.  I have spent the day reading about them.  (My ribs hurt too much to do much else.)  As often has been the case over the past few months, I quickly found myself in over my head, trying to tread water in a deep puddle of thick, sticky biology.  I will keep trying, but I don’t expect to understand very much very soon.  Nevertheless I want to acquaint you with a creature I have just encountered.  As you know, mice are very important in cancer research.  We have previously encountered the transgenic glowing reporter mouse (blog entry for 7/9/12).  Now I have met the “sublethally irradiated nonobese diabetic severe combined immunodeficient mouse”.  Further on in the article he/she is referred to simply as a NOD/scid mouse.    All I can say is – poor little devil.  Two observations:  (1) Cancer research would be nowhere without rodents, and (2) Cancer researchers may be excellent scientists, but they show little aptitude for poetry.



CANCER STEM CELLS: Another enemy?

LINDA IN YORKSHIRE, 2000
The Wrath of Henry VIII

I had planned to make August a biology-free month.  As I have written before, my plan was to spend most of the month in Alaska and in the Rocky Mountains, the latter period utilizing my new (to me) camper van.  But now, stuck at home with three broken ribs, two cats and a bruised ego, I might as well try to do something useful.  It remains to be seen if what I am about to do actually is useful, but writing about cancer certainly is preferable to watching daytime TV.

In all the reading and thinking about cancer stuff that I have been doing, I guess I have been searching for a magic bullet – some key to the origin or survival of cancer that could be attacked effectively, eradicated  and – viola! – free mankind of cancer forever.  (Actually, of course, I have been thinking of womankind and ovarian cancer most of the time.)  I have become excited in turn by the possibility of designer drugs based on genomics, aspirin (!), shutting down the blood supply to growing tumors, nanoparticles, killer T-cells, miRNA, fiddling with the activity of mutant Myc genes, and lastly, telomeres.  You can track this evolving enthusiasm by starting at the beginning and reading all 61 of my previous blog postings; if you survive, you will understand.  Now I have a new enthusiasm – cancer stems cells.

You know what stem cells are; they are cells that can turn into other kinds of cells.  If a cell in your skin dies, its place can be taken by the division of another skin cell.  However, that skin cell cannot divide and produce a substitute for a muscle cell, or a bone cell, or anything else – except another skin cell.  It has lost what the biologists call, I think, “potency”.  By contrast, stem cells are “pluri-potent”, meaning that they can turn into (produce) several different kinds of cells.  Embryonic stem cells, the subject of much inflamed political rhetoric, can turn into anything –they are “totipotent”.  What about cancer cells?

Well, there is a train of thought – called the “cancer stem cell hypothesis” - that holds that tumors are sustained and allowed to grow by the presence of their own stem cells.  There is evidence that the recovery of a tumor after it is blasted by chemo (or radiation?) is enabled by the presence of these “immortal”cancer  stem cells.  Three studies summarized by the NCI Cancer Bulletin for August 7^th (are you getting it yet?) confirm this idea, which has been circulating for quite some time but apparently is not universally accepted.  So,if the CSC hypothesis is correct, it would seem that we could cure cancer if only we could devise some sort of biochemical trickery to cause the cancer stem cells to croak.  No doubt this wouldn’t be simple; recall my Babushka doll analogy of a few blogs back. 

Stay tuned.  I have plenty of time on my hands so I will labor to get up to speed on this topic.  In the meantime: I know that some people reading this blog know vastly more about biology and cancer than I do.  How about “Commenting” if something I say is confusing, contradictory, or dead wrong?  I would appreciate it.

NOT OC: WHAT I LEARNED ON MY CAMPING TRIP

Garden in the village of Somewhere on Thames

The queen of England and the queen of my heart

Some of you know that I planned to spend most of August tooling around from campground to campground in my new camper van.  So why am I at home so early?   I will tell you.

The first week of August went well.  I visited the Kellys, in Cordova, where we  caught a few fish, ate many fine meals, and generally just relaxed.  Even the trips to and from were tolerable.  I find that it helps to carry a cane; people (as, TSA people and flight attendants) coddle you to an amazing degree.  I’m sure it’s mostly that they don’t want you dying on their hands, but it comes over as solicitous respect.  Whatever, I’ll take it.

Then a few days after arriving home I took off again in my van, bound for SE Idaho, where I joined about 15 or so fellow members of the Anza Desert State Park Paleontology Society  (hereafter the  Paleo group) for an extended look at the Paleozoic.  It went well at first, and we all had fun.  Here are some things I learned about camping with my little van:

              If you make coffee using a percolator,  buy coarse-ground coffee.

              If you do use a percolator, do not travel with it assembled or the rattle will drive you nuts.

  Before beginning a trip, assemble all your maps and store them in a convenient place.  When you    have used one, put it back – don’t simple pitch it somewhere. 

You may think you know how to get to someplace without checking the map (which you have lost), but you probably don’t.

If you are old enough to have lost some of your eyesight and most of your agility, don’t walk around after dark.

Which brings me to why I am home, instead of in Montana:.  One evening near the end of the period I meant to spend with the Paleo group I sat dozing in my folding chair until well after dark.  Then, when stumbling toward the van, I stubbed my toe on something, pitched forward onto a pile of rocks, and fractured three ribs.  Also, I broke my glasses and turned my right forearm into coarse hamburger.  I have camped all over two continents for over 50 years without serious injury.  I wonder what was different this time?

Anyway, after two full days of unpleasant highway driving I am home.  I stopped at the emergency room in LaGrande, Oregon – without a doubt the most pleasant emergency room experience of my life. I left LaGrande with an X Ray, a brand new tetanus shot, another shot (pain meds),  two prescriptions, and a half-inch stack of official paper.   So here I am at home, filled to the earlobes with pain medication and looking forward to an indefinite period (“oh, it will take a few weeks”) of being useless.  But that won’t stop me from writing this blog; I have two NCI Cancer Bulletins to digest.

DEDUCTION, INDUCTION, & Babushka dolls

Linda threatens Amanda, 1007

Amanda is not impressed

Okay, I know that I implied (in my last post) that you were rid of me until the end of August.  However, I am at the Hutch, waiting for a phone call, and I am just not up to attempting another research paper.  So, I am going to write about some idle musings I had while riding the shuttle yesterday.  They concern some differences between the kind of science I used to do and what is done – well, a good part of what is  done – around here. 

The first difference is the sheer size of data sets.   The largest study I ever published described the paleomagnetism of the Sanpoil Volcanics, a ~ 50-60 MY old sequence of andesites in eastern Washington.  Ken Fox and I were P.I.s, and we had two graduate students.  We sampled 90 sites, each with 5 or so samples.  Each sample was cut into two or three specimens – but usually only one specimen per sample  was measured.  Demagnetization procedures required, say, an average of 5 measurements per specimen.  Thus, in all, about 90 X 5 X 5 = 2250 measurements were made, although only site-means (90) were reported.  Thankfully, the graduate students did the measurements!

Contrast this with an experiment I just ran upon, described in Focus, apparently a newsletter for Harvard Medical.  In this study, aimed at dealing somehow with the gene Myc, a well-know cancer troublemaker, nearly 75,000 things called shRNAs (short hairpin RNAs) were studied to find which were effective at “silencing” genes that Myc relies upon to do its dirty work.  They found 403 potential candidates, and ultimately settled on one of them – coded for by a gene called SAE2 – for reasons that were not specified.  Presumably work will proceed from there.  One suspects that the 75,000 measurements were made by some sort of expensive “high through-put” machine and not graduate students, who are less reliable than machines and moreover have to be fed.

The second contrast between what I once did and what I am helping to do now concerns a fundamental difference in, for want of a better term, scientific philosophy.  In our Sanpoil study we had deduced that dextral shear along the west coast of North America had affected continental crust fairly far inland.  To test this hypothesis we sought to detect clockwise rotation of the Sanpoil block.  The large data set merely allowed us to be extremely precise.  By contrast – and given the usual caveats regarding my severely limited understanding – the Harvard shRNA  Myc study seems largely inductive.  They must have known that some types of shRNAs have the capacity to interfere with the oncongenic activities of mutated Myc, but they chose simply to test the entire kit and caboodle to find which ones.  All 75,000 of them!

This is motivated by practicality; at least some aspects of cancer biochemistry seem to be so intricately involved that pure deduction just won’t work.  In my geological example we already knew that relative motion between the North American and Pacific basin plates had generated shear in coastal North America; we simply wanted to see how far inland it extended.  Piece of cake!  But cancer research, it seems to me, is like one of those Russian Babushka dolls.  Every time you succeed in opening one doll there is another inside to work on.  Or two, or three, or – lots.  Consequently, if we wait until we understand the biology well enough to deduce what might work, a lot of people will have died.  So, God bless the through-put machines! 

Keep on advocating.



MORE CANCER RESEARCH IN THE NEWS

Linda and bovine friend

Isle of Skye

1999

Page A2 of the Wall Street Journal for July 27^th contains an interesting, understandable, but slightly discouraging article about brain cancer.  It appears that some common and highly aggressive brain cancers – called glioblastoma – are caused by a genetic malfunction involving the fusion of two normally separate genes – FGFR and TACC.  To satisfy your curiosity I searched out the meaning of these acronyms.  FGFR  stands for fibroblast growth factor receptor, and TACC is code for – believe it or not – transforming acidic coiled-coil.  Alone these genes serve useful functions, but if a molecular mistake occurs and they fuse, you’ve got a particularly nasty oncogene. 

The research described in the Journal was performed at Columbia University and published in Science.  The usual cast of thousands were involved – 24 in this case.  (Did you know that in med pubs the principal author is listed last?)  In it they report that three out of 97 human glyoblastomas investigated contained the fused gene.  When they extracted DNA from these tumors and injected it into mice, 90% of the unfortunate little fellows developed cancer.  Further experimentation showed that when the infected mice were treated with existing “FGFR blocker” drugs (already approved for certain types of cancer), their life-expectancy doubled.  That’s about all I know about the subject; I’ve got some papers to read the next time it is too wet to be outside.

So, I could let myself get discouraged.  The average life-span of a human being with glioblastoma is 14 months; all this work to stretch it to 28 months?  And that supposes that the mouse results translate into humans, which is by no means certain.  Also, only about 3% of this nasty kind of cancer is caused by FGFR-TACC fusion; what causes the other 97%?  To heck with it; I’m going for a walk.

Oh, by the way…  I am going on my summer drive-about in a few days and won’t be back at the blog until early September.  Keep on Advocating!

  

STROMAL QUISLINGS (figure THAT one out!)

Linda waits up for Santa Claus
1970

The latest NCI cancer bulletin (7/24/12) is filled with useful stuff, I’m sure, but is short on the reports of direct, blood-thirsty assaults on cancer that keep me engrossed.  There is one article of real interest, but trying to do research on it keeps putting me to sleep.  It appears that there is a gene, BRAF by name, mutations of which are found in many cancers.  Something like 80% of melanomas have it.  There are drugs available to disable the proteins “coded for” by this mutant gene – the chemical names of these drugs  all seem to end in “…ib”, no doubt for some perfectly sound reason.  Anyway, the ib drugs slow the progress of cancer, but they don’t actually cure it.  A new study (the usual cast of thousands – 18 authors in this case) indicates that the problem lies with the “tumor microenvironment”.  Specifically, cells of connective tissue apparently secrete a protein called HGF which protects tumor cells from the ibs.  If these connective tissue cells were people in, say, wartime France they would be shot as collaborators.  If there ever was a maladaptive trait, this has to be one.  How come evolution hasn’t taken care of the problem?

SUMMERUN NORTH 2012

The inaugural Summerun North was run at Bellingham's Marine Park, with 19 participants ranging in age from 4 to 93. The winning time for the ~ 3 mile "race" was posted by Woody; 1 hr 5 minutes.  However,  Woody (not shown) stopped to play on the swings and was pushed the rest of the way in a wheeled contraption by Sally, his mother (also not shown; probably chasing after Woody). The sky was murky and a little drizzle fell, but the hotdogs were excellent. Note the snazzy "Linda's Team" T-shirts.

We hope to have another Summerun North next year. 

Today is the one-year anniversary of Linda's burial.