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. 

WHO OWNS YOUR GENES?

Nord Kap (northern Norway), 2004

The guy is a Sami (Laplander), and the beast is a reindeer.

He poses outside a small store that sells tourist stuff.

When we drove up he was smoking a cigarette and looking pretty un-Sami,

This post lies at the intersection of two of my more conspicuous channels of incompetence: biology and law.

I have confessed my biological failings previously, more than once.  As to law: I was admitted to Stanford law school during my junior year.  In spring quarter, to get up to speed, I took a business law course.  I did horribly!  I was dumb!   No matter how I tried, I just couldn’t think like a lawyer.  Thank God I found out in time!

So, anyway, in today’s (7/20/12) Wall Street Journal, p. A3, there is an article entitled “Court to decide whether genes can be patented”  It appears that an outfit called Myriad Genetics, Inc., is being sued  by, among others, the ACLU.  The suit made it all the way to the Supreme Court, which kicked it back to a lower court for review.  The eventual disposition of the case is not at all clear.

The Journal article confuses me.   Obviously nobody can patent a gene – we all have them, we always have had them, and I doubt if even Hitler or Kim Jong Eun could make us lease them from anybody.  I can’t figure out if what they have patented is “natural” – taken from a human being – or artificial – built up in a test-tube.  It appears that Myriad has a patent on the actual gene-thing, and not – as I perhaps could understand –the process of using it. Apparently the rule of thumb is that you cannot patent either a “natural product” or a “law of nature.”   So I used Google to dig a little deeper.

The genes in question are BRCA1 and BRCA2.  The BRCA part stands for breast cancer.  A woman with a mutation in either of these genes is significantly more likely to contract breast cancer than an equivalent woman with her BRCA genes intact.   The BRCA1 genes, and its significance, were discovered by an academic researcher at U.S. Berkeley in the late 1980s.  The BRCA2 gene and its function were discovered some time later, at U. Utah.  Still later it was discovered that the BRCA genes also function in ovarian cancer.  It should be noted that Myriad Genetics was founded in 1991 and participated in the research establishing the BRCA genes as bad guys.  Two of the founders of Myriad were academics, from the U. Utah and Harvard.  The latter was a Nobel Laureate.

Apparently Myriad cloned the BRCA genes, and uses them in their test for mutations.  The cost of such a test is said to be about  $3000, although Myriad insists that all but $100 will be paid by the patient's insurance company (assuming, of course, that she has one.)  The claimants in the court case says that, because of the patent, patients are prohibited from obtaining a second opinion – and, of course, with no competitors, there is no incentive for Myriad to reduce their price.  So, as my mother would have said – a pretty kettle of fish!

I don’t have any profound, or even well-informed, opinions on this matter.  Obviously you shouldn’t be able to patent a law of nature, but doesn’t it make sense to allow a patent on a means of using it to affect something or other of importance to human beings?  Drug companies spend tons of money on research.  Most drug start-ups lose money for years, but hang on in the hope that something or other will turn up.  Shouldn’t they be allowed to recoup their expenses, and even strike it filthy rich (on the grounds that truly filthy riches will inspire other smart biochemists to find, and be able to profit from, something else important?)  In an ideal world the government, or the Bill & Melinda Foundation, would amply fund pure AND applied research, and the drug companies would make their money by manufacturing & distribution, just like they prosper from toothpaste and mouthwash.  But in the world we live in the government is profligate in some areas, stingy in others, subject to politics – in other words, totally unreliable.  And even Bill and Warren and all the other rich philanthropists can’t close the gap.  That is partly why prominent academic biochemists form companies like Myriad. Why scrape by with a Harvard salary when you can form your own company, do the same research, and become – you guessed it – filthy rich?  So, is it wise to slap down Myriad?  It may stifle research there, and elsewhere.  Or maybe not.  What do you think? 





NOT OC: Linda's Team, Part 4

Linda, niece Rebecca, brother Richard

Diablo Lake, 1978

Just a reminder that Summerun  North occurs this Sunday, 10:00 am to 2:00 pm, at Marine Park (in west Fairhaven).  It is a quasi potluck affair, which means that we will provide food enough so that no one goes away hungry, but healthy and/or tasty contributions will be appreciated.  Please see my post “Linda’s Team: Part 3” for further details.  One lucky participant will win a snazzy t-shirt, if he/she is approximately my size.  We hope to see you there.  Myrl

TELOMERES, TELOMERASE &, of course, CANCER

Relaxing on the beach somewhere

1988

Boy, am I ever pushing the envelope on this one!  I am going to write about something important, but that, truthfully, I barely understand. If that. Thus, what follows will be grossly oversimplified.  I just hope that it’s not dead wrong.  If it is, please let me know.  Politely.    I find this stuff fascinating so – if and when I learn more about it – I will add Comments to this post.    That should be about enough humility, so, here goes.  To do it Wikipedia style:

Mitosis:  Cell division, which entails duplication of the cell’s DNA.  One peculiarity of this process is that the very end of the chromosome cannot be copied.  This might cause loss or modification of genes, which would be bad news.  Fortunately there exist things called:

Telomeres:   These are peculiar, semi-useless, non-coding repeat sequences of nucleotides (in humans the sequence reads TTAGGG, where T stands for thymine, A for adenine, and G for guanine. Thus, your personal telomere consists of “TTAGGGTTAGGG& etc.”, strung out on the end of your chromosomes.  So does mine.   (You may have no idea about the structure or composition of these “bases”.  Neither do I.  If curious, ask my grand-daughter Olivia, who is out on a fishing boat at the moment – no doubt studying diligently in her spare time.)  Ordinarily, in a gene, the sequence of bases has unsurpassed significance, because it provides the blueprint for the manufacture of proteins.  However, the telomere sequence codes for nothing.  It is there only to protect the important (coding) part of the chromosome.  But for each cell division part of it is hacked off, which leads to:

Senescence and death:  Sooner or later your telomeres will all be used up, and important parts of your chromosomes will begin to disappear, be changed, swapped around, welded together or experience other pieces of bad luck.  Pretty soon thereafter your cells will throw in the towel and die, and –eventually – you with them.  To me, it seems like the secret to eternal life is to somehow replace the eroded ends of the telomere.  Oddly enough, there is a molecule capable of doing just that.  It is called:

Telomerase:  This is an enzyme that rebuilds the telomere.  However, in the normal course of things it is active only in fetal cells and things called “adult stem cells”, one of which resides in your bone marrow and renews your blood supply.  These have telomerase, but normal body cells don’t – which is why they grow old and die.  Interestingly:

Cancer cells:  At least many of them, have plenty of telomerase.  This is why they can go on rapidly dividing and not run out of telomeres and die.  Bad planning, it seems to me.  Anyway, it would appear that attacking telomerase in cancer cells is a promising approach to cancer therapy.  So says my 10-year-old biology textbook.  Even older research articles I’ve seen agree.  Then why is cancer still around?  I guess you can’t get at the telomerase in cancer cells without doing damage to essential adult stem cells elsewhere.  There ought to be some way to target the damned things.  Let’s get cracking!

This is quite enough biology for one bite.  Sorry.  I got carried away.