TALC

Linda enjoying another baby

Talc is in the news; Johnson & Johnson has been ordered by a jury to pay $72 million to the family of a woman who died at 62 of ovarian cancer.  She was a longtime user of talcum powder, and her suit contends that this was the cause of her disease.  Needless to say, J & J is appealing.  $72 million is pocket change to J & J; clearly they are fighting to retain a profitable product.  They will do so if they can demonstrate that talc is safe, presumably by means of clinical trials.  So, job opportunities galore for statistically minded biologists.  In the meantime; what to think?

I have written about talc and lawsuits before: http://ljb-quiltcutie.blogspot.com/2015/05/of-torts-and-talcum-powder.html.

So what is talc, anyway?  Chemically it is a hydrous magnesium silicate, formed from common magnesium-bearing minerals such as olivine, pyroxene and serpentine by metamorphism in the presence of water and carbon dioxide.  It is the softest natural mineral.  It usually occurs in extremely small grains, often in the company of asbestos.  It is a principal component of soapstone.  And, it often can be found in small containers next to piles of diapers.

Well, we all know that asbestos can cause lung cancer, but it appears that asbestos is not central to this issue because asbestos in talc has been sought out and eliminated since the 1970s.  However, asbestos remains an element in the dispute: asbestos is deadly because of its small grain size; it can lodge in the lung and cause genetic changes that lead to cancer.  Well, talc also forms tiny grains; could these tiny grains lodge in ovarian epithelium, cause genetic changes, etc.?  What is needed is scientific proof – principally in the form of clinical trials.  And here is where things get ugly.

Glossary:

Case-control study:  A study which matches individuals who have a condition with another, as like as possible, who does not have the condition.  This is a retrospective study: subjects are asked to think back and report how often and how intensely did they do something-or-other, such as smoke cigarettes or use talcum powder.

Recall bias:  The likelihood that people with the disease are more likely to report the activity under study than those who are free of the condition.  I explain it badly, but you get the point.

Cohort studies:  These are prospective.  A cohort is formed (for instance, all women named Alice born in New Jersey in 1948).  This cohort reports periodically on the thing under study – talcum powder use, for instance. After a suitably long time the statisticians are summoned to see if there is a “robust” correlation that MIGHT reflect cause and effect.  Recall bias is eliminated in cohort studies, rendering this approach more reliable.

So what do these studies indicate?  One researcher cited avers that the case is closed and has been for some time: 20 well-executed case control studies published over the last 30 years agree that talc usage is associated with increased incidence of ovarian cancer, by as much as 30%.  Recall bias is cited by some, but dismissed with considerable scorn by others.  To me it is noteworthy that there is a positive “dose response” in talc use: the more you use, the worse your odds.  Case closed, huh?

But wait.  Two recent cohort studies have shown no significant correlation with use of talc and ovarian cancer.  These were based on very large data bases, and presumably conducted properly.  So what the heck?

It may be significant that the scientist quoted has derived part of his income from Johnson & Johnson, but obviously he didn’t make the whole thing up.

Well, how might talc cause ovarian cancer?  As suggested earlier, maybe tiny talc grains become lodged in the ovary (or fallopian tubes) and cause long-term, localized inflammation, resulting in cancer.  Nobody has shown that this happens, but then – nobody has tried.  It is significant that many autopsies find talc grains where they should not be, including in ovarian tumor tissue.  

So what is the bottom line?  You guessed it: MORE RESEARCH IS NEEDED (!)  Experts disagree.  The American Cancer Society “calls for more research” and states that “if there is an increased risk it is likely to be small”.  30%, in my book,  is not small.

In the meantime, you can bet your prized collection of talcum powder dispensers that J&J is conducting a massive cover-your butt operation. If they knew that their product was not entirely safe and did nothing about it then they deserve their fate: bankruptcy.

Apparently there is a corn starch product that can sub for talcum powder.  Why not use it?

THE EMPEROR OF ALL MALADIES

Linda at five

Earlier I whined about my inability to sleep in the middle of the night.  My usual practice seems to be to fall asleep at about 8:00 pm and sleep like the dead until midnight.  Then, failing to go back to sleep, I take a “sleep-ease” kind of pill, get back in bed – and lay awake cursing my brain, which persists in dashing from topic to (unrelated) topic like a berserk housefly.  After an hour or two of this I get up, sit on the couch, and read.  I try to read something heavy, on the assumption that such stuff will wear me out quickly.  In an hour or so I find that my eyes won’t focus and the book persists in falling into my lap, so I stagger back to bed – where I lay, cursing my brain again, for a few dozen minutes.  And then I wake up, and it is morning.  I get 8 hours of sleep every night, and it only takes 11 hours to do it.  Young people: try not to grow up to be like me. 

It is not my exciting lifestyle that affects my sleep: much of each day I spend removing sand grains from mammoth bones.  Useful, perhaps, but not very exciting.

The book I have been reading is The Emperor of All Maladies, by Siddhartha Mukherjee.  I just finished it, for the second time.  I liked it before; I plan to rave about it now. 

First, Mukherjee:  He is a professor and cancer researcher with Columbia University.  One would have to concede that he is well educated: Stanford, then Oxford University as a Rhodes Scholar, and finally an M.D. from Harvard.  The book shows that he has had significant hands-on experience (“clinical practice”) with cancer patients.  From citations scattered throughout the book it is obvious that he has read many important books that I always thought I would read – but haven’t, yet.  He seems at home with many of the classical studies that I always meant to assimilate, sometime.  And he is a young guy, with little children!

Yeah, but has he ever climbed Mt. Baker, or run an ultra-marathon?

Okay, the book.  Its subtitle is The Biography of Cancer.  The long first section is history: what did our forebears know about cancer, and what did they do about it? Oddly enough, this is the part of the book that will – in places – make you wish you were doing something else.  Some of the ancient “remedies” described will merely strike you as pathetic; what can you expect from people before iPads?  However, “heroic” efforts involving surgery and chemotherapy performed fairly recently will make you cringe.  In my view, the best advice concerning cancer given before the mid-20^th century came from Imhotep.  Imhotep was the architect who built the step pyramid for King Djoser of Egypt’s 3^rd Dynasty.  That was about 4500 years ago.  Imhotep also was a physician, and was later worshipped as a god.   Concerning cancer, Imhotep said in effect: leave it alone.

But then the book gradually changes pace, dealing with recent developments.  The realization that cancers are the result of something gone haywire within a cell is fairly recent.  The impact of genomics on cancer is discussed.  Your old friends, oncogenes and tumor-suppressor genes, are skillfully and clearly described.  The why of mutation, and what we can do to decrease its prevalence, come into play.  There is a fascinating (well, at least to me) treatment of cascading chains of molecular interaction – and what we might be able to do to muck up the bad ones.  And there are lots of other plums of wisdom waiting for you to extract from Mukherjee’s beautifully crafted  pudding – but this has gone on for 619 words already, and you probably are eager to get back to the political news.  (Take heart: only nine months to go.)

In the end this masterful book gets a little too metaphysical for my tastes, but it also is pervaded by an aura of cautious optimism.  You close it with a smile on your face, and then go back to bed.  No, wait, that’s me, not you.

So, buy the damned thing, and read it.  You can get it from Amazon for $14.32 (hardcover), $11.25 (paperback), or $13.99 (Kindle).  Or you can beat Sidd out of his paltry royalty and buy it second hand through Abebooks for <$7.50, including shipping.

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

THIS MAY BE IMPORTANT

Borrego Springs, probably 2011

We have speculated, hopefully, several times about the promise of gene therapy in the ultimate eradication of cancer.  For instance, read this little gem:

http://ljb-quiltcutie.blogspot.com/2015/08/more-on-targeted-therapy.html

Well, NCI has – behind my back! – begun to get serious about it.  They are running a vast, far-flung trial to determine if targeting tumors according to their mutation(s) of origin rather than their organ of choice will do any good.  It works like this, more or less:  If you are unfortunate enough to have a solid tumor that no longer “responds” to standard treatment, and if your oncologist is on the ball, you can have a biopsied sample sent to one of four regional centers for genetic analysis.  If the analysis shows mutations in one or more genes known to be involved in various cancers, common and rare (there is a depressingly long list), and one for which some drug is already in use – you can get that drug.  Heretofore if a clinician wanted to try drug A, already approved for cancer B, on a patient with cancer C, he/she would have been forced to ascend a mountain of bureaucratic dung to do so.  Under NCI-MATCH, and under some (by no means all) circumstances, this no longer is the case.  If there is a drug developed for prostate cancers targeting mutated gene XYZ, and if your colon cancer has the same mutation – you can get the drug.  A rare example of common sense in action.

This trial already has enrolled its first 500 subjects and currently is closed while the statistics boys digest their preliminary results.  However, it will open again soon and will be seeking several thousand subjects.  It is free; even transportation costs are minimized by establishing lots of local centers.  For instance, Bellingham, WA residents  can simply take a bus to the local cancer center.  Even residents of my remote winter hideout, Borrego Springs, would merely have to surmount the Peninsular Ranges, to San Diego, a 90 minute drive.  Unfortunately, Linda’s sister Carolyn, located in Eureka, CA, would be required to penetrate the lowering  Redwood Barrier to present herself to the nearest participating facility in Santa Rosa, many hours away.  Perhaps this is part of the reason that she plans to move to Ashville, NC, where hospitals (and hillbilly bands) are everywhere.   

So read all about it yourselves.  This is progress, if still of  a miserably incremental kind.  I am somewhat depressed by the low bars seemingly set: “success” apparently is defined as merely slowing the growth of a tumor, or prolonging remission by a period measured in months.  No mention is made of ultimate mortality.  But, hell – it’s still progress.  Better than nothing.

http://www.cancer.gov/news-events/cancer-currents-blog/2016/nci-match-update?cid=eb_govdel

http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match#7

http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=773118#link/ContactInfo_CDR0000773118

MY STURDY LITTLE JEEP

This is not where I was yesterday, but represents the way I felt

Polish base, west Antarctica

Well, what did we learn lately?  I don’t know about you, but here is what I learned yesterday:

Do not strike large rocks with your sturdy little jeep.

Do not go to the far end of remote desert washes in your sturdy little jeep unless other vehicles are in company.

Do not be responsible for the transport of one or more women with planes to catch.

Carry plenty of water.

Yesterday I participated in a field trip sponsored by WAVP, the Western Association of Vertebrate Paleontologists.  I think I was invited along for geologic commentary, comic relief – and because I own a sturdy little jeep.  Anyway, all went beautifully until – at the end of the day, and at the remote end of Fish Creek wash – my jeep would not start.  Had I been alone I would have been up that well-known creek without a paddle.  As it was, we got sturdy jeep turned around and started using compression, and then with three women aboard took off for civilization.  About two hours later, having gone up the wrong wash once and later nearly driven off a cliff, I was home, women disposed of, drinking vodka and grapefruit juice.  I think the electrical system in sturdy jeep  was knocked all galley-west by abrupt contact with a rock.  I will find out just as soon as I can figure out how to get the damned – but sturdy – little thing to Tito’s Auto Repair.

So, from now on if I travel alone, which I will endeavor not to do,  I will at least tell people where I’m going.  And I will carry lots of water.



IN PRAISE OF ME, Part 2.

1951

2013

 How can this have happened?

There is nothing of any real importance in this blog, but that does not mean you should skip over it.  If you do it will hurt my feelings.

I want to brag and speculate a bit.  This is the 400^th entry in Myrl’sBlog.  Each entry contains on average about 350 words; the 400 thus sum to what you might find in a moderately long book.  I have been at this project since early in 2012 – for 1442 days to be exact.  Doing the arithmetic one finds one blog entry every 3.6 days, or roughly two per week.  All but a few of these blogs are intended to report some new development in cancer research.  In addition I have spewed out innumerable Comments, most of which also are intended to inform.  According to Google, which in this instance I profoundly  mistrust, these blog entries have been viewed just over 26,450 times – about 66 per entry.  Hits have come from 72 countries, ranging from 15,883 from the United States to one each for Moldova, Romania, and Kazakhstan.  Obviously I have not reached 26,000 people: a few relatives and friends certainly account for a greatly disproportionate fraction of hits, while at the same time the 1152 from the Ukraine should count for nothing because they certainly represent the footprints of a trolling algorithm and have nothing to do with real human beings.   The nearly 1800 hits purportedly originating in Russia are similar. Thus I don’t know how many people I have reached – but it’s more than a few.

So, have I done any good?  I think so.  Faithful readers should be familiar with the warning symptoms of ovarian cancer.  They know what kinds of activities and what familial histories predict a higher risk of ovarian (and breast) cancer.  They know what to ask the oncologist if – God forbid – they get a cancer diagnosis.  They know a little about current research trends in the battle against cancer, and they know where to go for more information. They can easily locate appropriate clinical trials.  And not least, all  faithful readers know what to do with that extra money burning holes in their pockets.  Thus, I judge my efforts not entirely feeble and useless – but for Linda’s sake I wish I could have done much more.

So, I will keep on blogging.  When I started this project I set myself the twin goals of curing ovarian cancer and winning the Nobel Prize by the time I was 80.  Now that I am sneaking up on 83 I think I had better reset the finish line.  Maybe 90 will do.  Do you think I will make it?  



MICE TO THE RESCUE - AGAIN

Cousins

 Schneiders and Joyces

Heron Island, 2009

 



My Kansas cousin Lynda and husband Pieter have been visiting me here in Borrego Springs for a week, during which time we toured many desert washes in my magnificently dirty little jeep.  They have just left, and the many pictures of Linda above my desk remind me that it is time to get back to work.  I always have believed in the overwhelming importance of having some  purpose in life; mine for some time has been to do something positive about cancer, no matter how little.  Those pictures of Linda help keep me going.

But that aside, I have run on an article in Techtimes that is of considerable interest.  To get the Web address out of the way first:

http://www.techtimes.com/articles/131592/20160208/researchers-discover-gene-family-that-converts-cancer-cells-into-aggressively-growing-stem-cells.htm

The work here is concerned with “cancer stem cells”, about which I have written several times previously, e.g.

http://ljb-quiltcutie.blogspot.com/2012/08/cancer-stem-cells-may-they-rot-int-hell.html

Some research people at Georgetown have been working with mice (what would we do without ‘em?) for years and have found a particular murine (i.e., mouse) gene called Sca1 that is associated with fast-growing, intractable cancer.  It seems that a set of human genes, called the Ly6 family, may play a similar role.  Ly6 is located at the same chromosomal location in humans as Sca1 is in mice.  Genetic testing by the Georgetown scientists indicates that Ly6 is abundant in tumor tissue but not in normal tissue.  Apparently mutated Ly6 imparts stem-like properties; rapid, out-of-control proliferation.  Why is not clear.  The article implies that this new knowledge may lead to therapies, but doesn’t explain how.  Maybe so.  Let’s hope.

Then things trail off into stupidity.  The concluding sentence reads “It….example of what happens when researchers share data, supporting the “Cancer Moonshot” proposal announced by President Barack Obama in his…….”.  For God’s sake, how do people get the idea that scientists hoard data?  If you are an academic scientist your very life’s blood is grant money, and the only way to keep it pumping is to publish your discoveries, complete with data, as fast as your fingers can fly over the keyboard!  There is certainly lots to be said for systematizing, simplifying and making generally available the contents of tissue and blood repositories, genetic scans and the like, but if medical researchers deliberately withhold their data  I must have spent my entire scientific life in an alternate universe.  Somewhere I read that Linus Pauling, having worked out the structure of an important protein, spent a day gloating that he knew something that nobody else in the world knew.  He published the next day. 

 

ZINC FINGERS AND PROGRESS

Linda, in the midst of chemo, entertains a

great nephew

Heron Island, Maine, 2009

A tip from Google Alerts to an article by one Maggie Fox published by NBC News has lured me into a downward spiral into the black depths of bio-genetics.  To get the reference out of the way:

http://www.nbcnews.com/health/cancer/gene-signature-could-lead-early-cancer-test-n512496

So, anyway, some people at the National Human Genome Research Institute, a part of NIH, have been looking for genetic markers that would reliably predict the presence of cancer in the absence of symptoms – and they may have found one.  They performed what I believe is called a GWAS – a Genome Wide Association Study – and found something exciting.  Specifically, they saw that tumors in the colon, breast and stomach, as well as in endometrial cancer all showed abnormal methylation near a particular gene, ZNF154.  Fifteen discrete types of cancer were involved.  Why this unusual methylation pattern exists is not yet clear, but present results strongly suggest that this observed association will be valuable for early detection.  They are testing it on ovarian cancer at the present time.

Okay, that’s all you really need to know.  However, it you want to follow my doomed spiral into biochemical oblivion, read on. 

First, methylation.  A methyl group is a molecule consisting of three hydrogen atoms bonded to a central carbon: CH₃ in chem-speak.  Methylation itself is the attachment of a methyl group to a specific spot on the DNA molecule, in order to “regulate” something – usually, shut off (inactivate) a gene.  Methylation is an important epigenetic process.  Read all about it here:

http://ljb-quiltcutie.blogspot.com/2013/08/epigenetic-apocalypse-now-i-warned-you.html

Now, how about gene ZNF154?  Well, ZNF is short for zinc finger.  Apparently there is what any sane observer would regard as a ridiculous number of ZNF genes.  Each codes for a protein that is characterized by finger-like protrusions containing a zinc atom.  These ZNF proteins perform a variety of functions: ZNF154 is described as a “transcription factor”, which I take to imply that it has something to do with “transcribing” the information on DNA onto a messenger RNA molecule.  In the literature I read the downward spiral continued, but I was already thoroughly drowned.  I wish I had studied biochemistry.

As an aside, heretofore “zinc finger” molecules seem to have been used to “edit” DNA, but this has been superseded by the CRISPR technique, with which you are  certainly familiar.

Also, the bottom of this article shifts direction and gives you some details about current Moonshot planning.  I worry that it will merely involve more money.  Cancer cannot be drowned in money.  Joe Biden: for God’s sake, read my blogs!