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.  

NOT EXACTLY OC. THE 2012 GEOLOGY NEWSLETTER

At Sue Broadhurst's wedding, 1998

She was always happy when other people were happy

I am at Fred Hutch with no QC-ing to do, so I decided to write another blog entry.  My initial idea was to write about telomeres, telomerase, aging and - of course - cancer.  However, it has become glaringly apparent that I need to do more study - a lot more study - to get this even remotely right.  So instead I'm going to post most of what I wrote for the Geology Department newsletter.  It describes my activities here, and flogs my blog to an audience of thousands (well, maybe a few dozen).  So that's it, below.

But I can't resist introducing you to a creature I just encountered while reading about telomeres.  This is the "TERT-green fluorescent protein transgenic reporter mouse."  This little fellow is important in telomere research, but I can't help but visualize a glowing-green mouse with a pencil, pad of paper, and maybe a cigar, hiding in a corner during - say - Watergate.   So, anyway, the newsletter entry:

Well, I blink my eyes and suddenly I’m nearly 80 and retired for 15 years.  I guess I could quote the old business about  “time flying when you’re having fun”, but it really wouldn’t apply for much of the last few years, until lately.

Have you ever heard of “The purpose-driven life?”  It is said that to maximize joy and satisfaction in life one must always have a useful project in hand.  Some presumably wise Frenchman whose name I can’t remember, and couldn’t spell if I did, put it that “Every man needs a project.”  Well, whoever he was, he seems to have been right, at least where I’m concerned. 

After Linda died I sat around a lot, staring at my toes.  I got fat, my arthritis got worse, my golf game went to hell; to put it bluntly, I felt like crap.  Then, about six months ago, I finally summoned the energy to do what everyone had been telling me to do – I went out to find somewhere to volunteer.  I tried the cancer center; they were “full”.  I tried the hospital: likewise.  I tried Hospice House.  They had a waiting list.  So, in desperation I aimed for what I really wanted to do in the first place: I asked the ovarian cancer people at Fred Hutchinson Cancer Research Center if they could use some unskilled labor - and a miracle occurred.  They welcomed me, gave me a card that opens all the doors, an office (better than anything I ever had at WWU), a computer, and a title.  I am officially a Research Advocate.  No money, of course, but all the office supplies and stuff that I can possibly use.  And their cafeteria is excellent!  I feel like a new man; I have a purpose in life, that purpose is pre-eminently useful, and it lets me work to eradicate the disease that killed my wife.  Wonderful!

What is a Research Advocate, you ask?  Well, that’s an interesting question.  Nobody seems to know.  Obviously I am supposed to “advocate” for cancer research, but how I do it seems to be up to me.  I can tell you what I do, but this wouldn’t apply to our other Advocates, none of whom I have ever seen.  I study a lot.  I read their papers and research proposals and try to provide feed-back.  (This is hard when you don’t really understand what you’re reading.  Hard, yes, but, it turns out, not impossible.)  I go to their seminars and keep my mouth shut.  (Sometimes they look at me and ask if I understand what they’re talking about.  I usually say “a little bit”, causing them to explain it in simpler terms.  I think it helps them clarify their thinking.)  It is always a little bit like “Alice down the biochemical rat-hole”, but it is fun, and I have the feeling that I’m useful.  I go to Seattle two days per week, stay with my daughter, and spend most of the day at my Fred Hutch office.  At home I study and write my …….blog.

Yes, I have a blog.  It relates my adventures as a geologist pristinely innocent of any kind of biochemistry, messing around in cancer research.  I try to make it funny, but sneak in some facts from time to time.  You should follow it.  The URL  is www.ljb-quiltcutie.blogspot.com, but you can get to it easier by Googling “Myrl’sBlog”. 

So, anyway, the trajectory of my life so far has been from Caltech, hoping to become a physicist, to Stanford, studying  to be a lawyer, to becoming  a geologist, to studying trees, then Egyptology – and finally, to cancer research.  I may not live to win the Nobel Prize in medicine, but I’m trying.  And I feel great.

     

FOR LACK OF ANYTHING SIGNIFICANT TO WRITE ABOUT

Linda with her good friend Janie Geffken, in Exeter, N.H.

That's Marion - Linda's mother - walking down the stairs.

1998

I have been trying to stimulate interest in cancer research here at the university.  It is a very steeply uphill endeavor for any number of reasons.  I have a notice on the door to my office which designates it as “Fred Hutchinson Cancer Research Center – Northern Annex”.  Under this is written: “ Come on in and talk about cancer.”  I guess I shouldn’t be surprised that nobody has responded.  I even offered to talk about tectonics and/or paleomagnetism, but they still scuttle on by.  My latest trick is to post a “Weekly Cancer Fact”.  I’m fairly certain that people read these, but they never come in.  I wonder why?

 So, anyway, I think I’ll post these “facts” now and then.  That way they won’t be completely wasted.

I would like to bring the picture posted above to the attention of Janie Geffken, but I don’t have her email address.  If anybody does, please let me know.

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Cancer-related random fact of the week  #4

Apoptosis:  Programed cell death.

Oncogene:  See below

 It is important that cells die.  As an extreme but amusing example – if a single E. coli bacterium divided every 30 minutes – but then lived on forever – after a few months the earth would be covered with the little slimeballs to a depth of about one foot.  And the slime coating would continue to grow.  In a few years it would be expanding outward at the speed of light.

Tumors represent uncontrolled cell multiplication.  Any gene that, left to itself, would result in uncontrolled cell division is an oncogene. Thus apoptosis is our friend.   Cancer is complicated, and I probably should have stuck with plate tectonics.

EGGS, CANCER and a HEALTHY BREAKFAST

Thoroughly enjoying our Norwegian cruise
That's wine in the glass.  At $8.00 per pop.
Good thing she preferred diet Pepsi

I have written so many of these blog things that I begin to forget what I’ve “covered”.  Repetition of topics probably isn’t such a bad idea:  it will enable the reader to judge how little I knew about the subject originally, and how little I’ve learned since.  Anyway, I started out to write about mice and cancer research, but vaguely remembered that I’d done it before.  I looked back through the blog and, sure enough, there it was: “Forget dogs, the mouse is man’s best friend” (3/12/12).  Oh well,  I’ll write about chickens instead.

You almost certainly didn’t know that egg- laying hens contract ovarian cancer.  Probably because a laying hen uses her ovaries every day (if she’s a good chicken), the poor birds get ovarian cancer at a prodigious rate: 15-20% for 3-year olds, and worse the older they get.  Also, egg-laying chickens seem to have some of the same blood-markers as humans.  That being the case, a group I have been reading about has devised a study called “The egg-laying hen spontaneous OVCA Model.”  It strikes me as ingenious; quick, cheap, effective, and in the end you can eat your experiment.

I wonder, though, if I would have the guts to eat an egg produced by a chicken I knew had cancer.  Given that so many laying chickens contract OC – and darned few egg farms have clinical facilities – I would guess that a substantial portion of the eggs we consume come from sick mothers.  I intend to forget that by tomorrow morning.

Myc: FRIEND or FOE?

Linda w/Carolyn's wildcat, 2001

I got the idea for this post from the Fred Hutch e-newsletter, and specifically from an article entitled “Orphan drug used for sleep disorders may be potent cancer fighter.”  The article describes the work of Dr. Carla Grandori, who looks (from the appended photo) far too young to be heading her own lab.  However, she is, and it seems to be doing good work.  In a biochemical nutshell:  There is a gene, Myc  by name, that is implicated in several types of cancer, including something nasty called neuroblastoma, which kills children.  Unfortunately, a direct attack on Myc is infeasible, for two reasons.  First, it is difficult to attack with the kind of “stable, small molecule that would work as a cancer drug”, and second, Myc is needed for normal cell functions, so destroying it throughout the body would be a bad idea. 

However, there is a way out.  Myc genes in cancer divide and multiply very rapidly, thus furnishing an enhanced opportunity for mutation.  To keep the Myc gene in fighting trim, so to speak, proteins coded for by other genes, probably called DNA repair genes, must undo the damage.  This means that one can attack the repair genes, or (more accurately, I think) disable the proteins they code for – thereby limiting repair and disarming the Myc.  It so happens that there is a drug already on the shelf – its name is CSNK 1 epsilon – which does this admirably well.  Tests on mice indicate that it is a powerful weapon against (mouse) cancer.  Although they don’t look much like us (mice are cuter), apparently our small furry friend is very like us genetically, so maybe CSNK-1e will help us, too.  It is to be hoped.  Interestingly, CSNK1e was developed to combat sleep disorders.  It didn’t work.

And now, as I have nothing better to do, I’m going to toss out some random thoughts.

1)  I am more than a little confused about something.  If Myc is needed for normal cellular processes, how come it sometimes causes cancer?  My natural guess would be – because it mutates.  But if there are repair genes that code for stuff to repair cancerous Myc genes, how come they don’t fix the original mutation?  Or is there something much deeper that I overlook?

2) In an attempt an answer  the latter question, I tracked down, printed and attempted to read the original article by Dr. Grandori and her twelve (12!) co-authors.  It might as well have been written in Lithuanian!  The abstract is comprehensible, though, and there are some interesting illustrations. 

3) There appear to be members of the human genome that are classified as “undruggable”**.  This means, it seems, that they code for proteins that lack receptors to which “small-molecule therapeutic  agents” (apparently the stuff of drugs) can bind.  This from an article by Andrew Hopkins and Colin Groom, published in 2002.  There are about 30,000 genes in the human genome, and as many as a third  may be druggable.  Of course, you only want to drug the bad guys.

4)  Cancer research certainly relies heavily on fancy machines.  Dr. Grandori’s group investigated about 3,300 druggable genes, using a method called “high-throughput automated approach for testing of an arrayed siRNA library”.  siRNA means “small interfering RNA, and I know what most of the other words in that description mean – but I have no idea how her process works.    But, I’ll bet it’s expensive.  Maybe not as much as a battleship***, but surely as much as a light cruiser.  

**Another way to be “undruggable”, it seems, is to code for something absolutely essential.

*** This refers to posting “Musings”, from 6/13