MUKHERJEE on EPIGENETICS

We are fortunate to live on the migration

route of the fabled Arctic flamingo

I am beginning to believe that Siddhartha Mukherjee, MD, is twins – or possibly triplets.  Not only has he written two books, one of which I have twice read and greatly praised, the other sitting half consumed on my reading stand  –he maintains an impressive research career (32 scientific pubs since 2011), and still has time to write articles aimed at you and me.  And he writes them well.  I stumbled on one today while waiting to have my cranial skin cancers frozen.  It is a treatment of the subject of epigenetics, which I have mulled over with you many times previously.  For instance:

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

I am not going to attempt to summarize Mukherjee’s essay.  It is clear, understandable, and even – at least for a fanatic like me -  entertaining.  It also is long.  Those of you with a serious interest in biochemistry and/or molecular genetics, and who lack a PhD in both subjects, are urged to click on the following link:

http://www.newyorker.com/magazine/2016/05/02/breakthroughs-in-epigenetics

PS: no melanomas, but a cryogenically preserved brain. 

NOT A GUY THING

Lunch at Crater Lake

This is really not a guy thing, but I have a nice picture I want to use and this is the best “news”  I can find.

There is a female disease called endometriosis that is often confused with “having a bad period”.  It is caused by uterine tissue growing outside the uterus, where it is not supposed to be.  Many (most?) docs don’t recognize it at first and, if you are worried it is up to you to jog their memories.*  There seem to be therapies for endometriosis, including surgery, but the article…..

http://thestir.cafemom.com/healthy_living/198268/5_things_you_didnt_know

….. is vague.

One of the bad aspects of endometriosis is an increased probability of ovarian cancer.

http://www.healthywomen.org/content/ask-expert/1760/endometriosis-and-cancer-risk

On another subject, how ‘bout them Mariners?  Leading their Division, then come home and drop three straight to the worst team in baseball!

*"Oh, I'm sure you're right, but I read somewhere about something called endometriosis that is just like a real bad period.  I've had this for a long time.  Maybe we should check it out?"

MOLES & MELANOMAS

Linda points to her fossil camel tooth

Much of my life has been spent outdoors.  When I was a kid I worked Saturdays and all summer in the lumberyard part of the Beaumont Hardware & Lumber Company, under the broiling Southern California sun.  Much of my recreation, until lately, has centered on hiking in the mountains.  For quite a while I ran many hours on local roads, trails, and  available tracks.  As a geologist I did field work in sunny places like Chile, the Caribbean, and the Greek islands.  The point is: in all that time I never wore a hat

.  (I wear one now – to keep my head warm now that my hair has fallen out,)

And now I am paying for it.  Every six months or so I go to the doctor to have the latest crop of skin cancers removed from the top of my head.  They come off nicely when squirted with liquid nitrogen.  The current batch (I can feel a bunch) will die early next week.

But of course, I worry about melanoma.  No tricky arrangement of mirrors will enable me to study the top of my head, but I examine the moles I can see very carefully.

AND SO SHOULD YOU.  Here is a handy guide to moles, melanoma, and everything in between, brought to you by the NIH.  Bookmark it or something so you can consult it the next time a scary looking blotch appears on your skin.

http://analysistools.nci.nih.gov/nevustool/?cid=eb_govdel

REMISSION, RELAPSE. Then what?

Happy

Far too many ovarian cancer histories go like this.  First, the cancer is diagnosed, often by accident (OVCA symptoms are notoriously subtle), and found to be in an advanced state (Linda was stage 3C, indicating that the original tumor had spread throughout her abdomen.)  The first therapeutic step involves so-called “debulking surgery” – all visible traces of the cancer are cut out.  Next comes “adjuvant chemotherapy”, involving a cocktail of drugs that, hopefully, will kill any remaining cancer cells.  Workhorses among these drugs often are platinum-based.  Normally this puts the patient into “remission” – that is, no trace of the disease can be detected.  (Remission often is monitored by periodic determination of the level of the protein CA 125 in the blood.  “Normal”, which varies considerably, ranges from 0 to 30 or so; Linda was at 650 when diagnosed and at 6 after treatment.)

In remission the patient can live a normal life.   Her hair grows back, she regains strength and mobility, she can be happy.  However, after a few months or years in all too many cases remission is gradually lost.  In Linda’s case her CA 125 count remained at 6 for about two years.  Then, one month it rose to 8.  No problem, right?  The next month it was 15.  The cancer was coming back.

Apparently the cisplatin-based drug cocktail was effective initially, but had left behind a few cancer cells that were “immune”, rendering it futile to repeat the original chemotherapy.  In Linda’s case another selection of drugs was tried, resulting in only a short, partial remission.

Well, researchers at the University of Michigan may have discovered a way to deal with this apparent immunity.  They found that fibroblasts (a type of cell involved in connective tissue) located in the tumor’s microenvironment acted to prevent buildup of platinum in the cell.  They also found that immune T cells could pry open the fibroblast barrier, thereby allowing the platinum poison in to kill the cell.  (Mice, again, of course.)

  My reading of this is two-fold.  Maybe administering T cell based immunotherapy along with standard platinum-based chemo would wipe the cancer out in one fell swoop.  Barring that, maybe T-cells would make it possible to use the same drugs after an initial remission, thereby prolonging remission indefinitely.  More I cannot say; there are important parts of these two articles that I simply don’t understand.

And here is something else I don’t understand: how in heck are we supposed to regard the process of  “relapse”?  I have written about “cancer stem cells”; are there such, and how do they operate?  Also I keep reading about the accelerated rate of mutation in cancers, presumably making it difficult to eradicate the beast completely before it changes.  Now I read that an army of misguided fibroblasts promote relapse by combating cisplatin.  Are all of these things true?  If so, God help us.

http://www.genengnews.com/gen-news-highlights/t-cells-help-reverse-ovarian-cancer-drug-resistance/81252753/

http://www.siasat.com/news/reversing-chemo-resistance-ovarian-cancer-immune-cells-961322/

May 22, 2016

In our hearts forever

Today is the fifth anniversary of Linda’s death.  I don’t feel up to writing something new, so I will modify and re-post a blog from three years ago.

On this fifth anniversary of Linda’s death I can do no better than to repeat what I wrote on May 22, 2011.

My beloved companion of 30+ years left today at 4:20 pm.  She had struggled bravely for days, but in the end her going was peaceful and, in its way, almost beautiful,  If there is a heaven she is surely there, with the mother she hasn’t seen for five years and the father she has missed for over fifty years.  There will be a celebration of life but I don’t know when*; you will all be informed.  Hospice House is a wonderful institution.  Your friendship is a great blessing.  Life can be painful, but I guess it’s worth the effort.

As for me, the pain is still here, but I have learned to deal with it.  And I continue to work to the best of my poor ability to hasten, if by only a few hours, that wonderful day when no woman ever again has to suffer what Linda suffered, and no man will be forced to stand by, helpless, and suffer the agony of watching his beloved wife die of ovarian cancer, and be powerless to intervene.

If you would like to make a donation to ovarian cancer research, please do it through Linda’s tribute page:

http://engage.fredhutch.org/site/TR/PersonalFundraisingPages/General?px=1148821&pg=personal&fr_id=1573

*It was held on July 24^th, 2011.  About 65 people attended - a small fraction of those who loved her.

STARVE CANCER TO DEATH

An anniversary, probably early 80s

In our little house on Cowgill

Of me, note hair and ability to button jacket across belly

She was beautiful, of course

So, let us consider ways to kill a cancer:

                Cut it out (surgery)

                Burn it up (radiation)

                Poison it (chemotherapy, including the targeted  sort)

Sic the immune system on it (immunotherapy)

Of course, these weapons can be combined.  For instance, in OVCA the “standard of treatment” seems to be debulking surgery followed by adjuvant chemotherapy (two obscure adjectives there, which I am sure you know.) .  It doesn't work very well.

Well, according to this article

http://www.nytimes.com/2016/05/15/magazine/warburg-effect-an-old-idea-revived-starve-cancer-to-death.html?smprod=nytcore-ipad&smid=nytcore-ipad-share&_r=0

there is another way, long forgotten but now resuscitated and considered  innovative and exciting:

                STARVE IT TO DEATH!

It appears that cancer cells are sugar-hogs.  They use so much glucose that they can be identified on a PET scan by glucose concentration alone.  Furthermore, they “burn” it inefficiently, using a process called fermentation (deriving energy from glucose anaerobically).  This process should be familiar to many marathon runners.  It results in the accumulation of lactic acid at about mile 22, accompanied by a build-up of the question “why did I ever start this race in the first place?” in the brain.*

Much of this article concerns the life of Otto Weinberg, a German Jew who thrived in Berlin during the Nazi era,  Weinberg discovered the fact that tumor cells are glucose hogs; this is known today as the Weinberg effect.  He devoted much of his life to developing a “universal” cancer cure (about 80% of all cancers exhibit glucose gluttony).   It appears that he escaped the gas chamber because Hitler and some of his cronies had a morbid dread of cancer – and Otto Weinberg was considered the pre-eminent cancer scientist of his day.

He also had a magnificent ego.  For instance, when informed that he had won the  Nobel Prize he retorted “about time”.  He is also said to have died under a wall inscription that read  “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die”  Apparently he steadfastly rejected the foolish notion that cancer had anything to do with genes.

Sadly, much of the last part of this (perhaps overlong) article is difficult to follow.  Apparently efforts are underway to create cancer therapies utilizing the Weinberg effect, but how they hope to work is unclear to me.  Insulin plays an important role, it seems – too much insulin: bad.  But I will leave it there.  Read the article and see for yourself..

*For more on the mysteries of cellular metabolism, consult explanations of the Krebs cycle.  And if you do figure it out, please explain it to me.

SOME DULL BIOLOGY. Read it anyway.

Heron Island, Maine

2009

HERE are some useful facts:

                Amino acids are organic molecules.  There are 20 different types.  They have names like tyrosine and glutamine.  They all contain a carboxyl group (CO₂^-) and an amino group (NH₂₎).  They differ in what are called “side chains”.

                Proteins are long strings of amino acids.  The sequence of amino acids in a protein determines its shape, which in turn determines its function.

                The amino acids in a protein are held together by something called a peptide bond.  In chemistry, “bonds” stick things together. How it occurs in this particular instance is of no earthly interest to us.

                Because proteins are strings of amino acids held together by peptide bonds, sometimes they are called polypeptides

Polypeptides may have hundreds or thousands of peptide bonds; the ones we are going to discuss have five.

Now, wasn’t that fascinating?

Having written the above, I took the trouble to actually READ the article that inspired it, and guess what?  I needn’t have bothered.  Here, see for yourself:

  http://medicalxpress.com/news/2016-03-small-peptides-ovarian-cancer-fronts.html

Here is the gist.  Scientists from Boston, Norway and Cornell have developed a new prospective weapon against ovarian cancer.  Back in 2009 they determined that a protein called prosaposin was effective in blocking angiogenesis (formation of blood vessels) and inflammation in the “microenvironment” of solid tumors.  From this stuff (prosaposin) they extracted a five-amino acid chunk  they call a psaptide.  .  Then they modified this little devil in two different ways, both of which make it more potent. This psaptide works by “stimulating” some substance called thrombospondin-1 (TSP-1), which does the actual work; kill cancer cells

I love these medical words: they drive Spellcheck crazy.

Anyway, many mice have died and the method looks promising.  Make it so!

THE DEATH OF CANCER?

Oregon Coast, 2007

Now here’s an optimistic take on cancer.  At least for most of you; for me it’s irrelevant:

http://www.fool.com/investing/general/2016/03/13/could-cancer-deaths-really-be-eliminated-for-peopl.aspx.

Warning:  The origin of this article is Motley Fool, a stock market pub.  Its purpose is to alert you to potential profits in Pharma stocks.  So, if you don’t have money smoldering in your pocket, only read the first page.

The gist of the article is as follows:  Two optimistic Brit onco-scientists predict that cancer will be eliminated in people under 80 – by the year 2050.  As I already am over 80, and would be 117 years old in 2050, they are not talking to me.  But, hey, my kids, grandkids and great grandkids will be here then, so I hope they (the onco-docs) are right.  Here are the reasons for their optimism:

 

1)      Reduction in smoking rates.

2)      Personalized medicine, based on genetics.

3)      Earlier diagnosis.

4)      Better drugs.

5)      Healthier lifestyles: less obesity, more exercise, less booze, lots of red wine.  (No – I made that last bit up.)

As to #4 – they will tell you what to buy to get in on the bonanza.

In passing, Dr. Vince DeVita – author of The Death of Cancer  (http://ljb-quiltcutie.blogspot.com/2016/03/warts-and-all.html) probably would agree with this assessment – although not necessarily with the stock tips.

MORE PROGRESS

Hard at work

Linda’s sister Carolyn alerted me to this article, from Fox News via Yahoo!  It may be very important, or it may prove to be another promising idea that went all catawampus.  Let’s hope for the best,

http://www.foxnews.com/health/2016/05/05/researchers-develop-human-derived-antibody-that-appears-to-destroy-cancer-cells.html

So, folks from Duke University have been pursuing an idea that seems to me to be a contribution to the hot field of immunotherapy.  We have talked several times before about “checkpoint inhibitors”.  Here, for instance, is my first attempt to explain them:

http://ljb-quiltcutie.blogspot.com/2015/02/please-read-this-fascinating-little.html

Briefly, checkpoint proteins lodged on the exterior cell wall of normal cells prevent the attack of immune T cells that circulate in the bloodstream.  Invading organisms, lacking such signals, are quickly gobbled up.  Diabolically, cancer cells manage to protect themselves by exhibiting these same checkpoint proteins.  However, molecules can be devised that bind to the checkpoints and render them non-functional.  The T cells thereupon attack.  Query:  Doesn’t that leave healthy cells at risk, also?  Hello, bad side effects.

Well, the Duke people seem to have done something similar.  They are attempting to disarm a protein called CFH (Complementary Factor H), which, they say, protects the cancer cell from immune attack.  They also say that CFH is present only on tumor cells, not on healthy cells.  The immune weapon here seems to be white blood cells (leucocytes) which also can kill the bad guys.  Second Query:  Does this mean that side effects would be reduced, or absent?

Third Query:  Is CFH a part of a cancer checkpoint?

So, the Duke guys have tried their weapon out on multiple cancer cell lines, as well as a host of long-suffering mice.  How close they are to human trials is not discussed.  So far, though, so good.  Interestingly enough, they aren’t seeking to totally eradicate the cancer cells, only to keep them in check.  Apparently if they do this for a time the natural immune system will wake up and finish the job.  Let’s hope.

Thanks for the tip, Carolyn.



I AM CONFUSED

Pretty backdrop

Wonder where it was.

Okay, this is getting ridiculous.  I used to think that all it took to start a cancer is a mutation in a single important gene.  Take the “tumor suppressor” gene TP53, for instance, TP53 codes for the protein p53, the so-called “angel of death”.  P53 tells defective cells when to die.  Absent a functional TP53 gene, a cell will just go on dividing without limit – turn cancerous.  Or so I thought,

Well, it turns out otherwise.   Some people at UW and Fred Hutch have developed a super-fast, super-accurate method of sequencing DNA, and have found loads of mutated cancer-relevant genes in perfectly healthy people.  People with cancer have more, but it appears that we all have some.  So, I don’t get it; what caused Linda to get cancer, but not me?  The article refers to something called the burden of potentially cancerous mutations, but doesn’t explain it.  Maybe if I went to medical school…….

http://medicalxpress.com/news/2016-05-prevalent-cancer-associated-mutations-apparently-healthy.html