of CANCER STEM CELLS, MICE, AND SHMOOS

 

Linda and lobster pots

 

Newfoundland, , 2001

 

Are you old enough to remember the cartoon strip Li’l Abner?  It was drawn by Al Capp and was one of the funniest things around; often it was the only compelling reason to open the Sunday Riverside Enterprise of my youth.    Anyway, for a time it featured the most benign creature ever conceived   – the Shmoo.  The Shmoo was a small, round, smiling creature that existed only to ascertain  the wishes of humans (seemingly by mental telepathy), then happily turning into whatever was wanted.  If you were hungry, for instance, the Shmoo would suddenly become a hamburger.  Presumably if you were vegan it would become a vegi-burger, with a certified organic, gluten-free, whole wheat bun.  

Well, there aren’t any Shmoos in this world, but there ARE laboratory mice. The laboratory mouse has given its life to benefit humans for many decades.   More have just died to give us important information about cancer stem cells.  They may not have died gladly, but no doubt they went straight to mouse heaven with no pause to clear purgatory.

So, anyway, the British journal Nature has published an important paper about the role of stem-like cells in epithelial ovarian cancer.  The principal author appears to be A. Nikitin to whom the Marsha Rivkin Center gave a nice grant in 2011.   The gist of the matter is that his research team seems to have shown that there are stem-like cells lurking in “niches” in the epithelium of ovaries.  They have a positive role; they repair small tears caused by ovulation.  However, this research also points out that they are particularly susceptible to cancer-causing mutations.  (This may account for the fact, that the more you ovulate, they greater your chance of contracting ovarian cancer.)    They investigated this hypothesis by first detecting and then  isolating mouse epithelial cells with stem-like properties, then injecting them into eight lady mice that previously had several tumor-suppressor genes “knocked out”.  (How this is done is just as much a mystery to me as it is to you, of course.)  Anyway, seven of these unlucky mice developed ovarian cancer.  

I can’t actually discern any immediate applicability of this discovery to human OVCA, but the more we know about the enemy, the sooner we can defeat him.  I got that quotation from The Art of War.  Not really, but I’m sure it’s in there somewhere.

I previously blogged about cancer stem cells on 8/22/12 and again on 8/26/12

 

Do you want to read more about ovarian cancer stem cells? 

http://www.medicalnewstoday.com/articles/257367.php

 

Do you want to know more about Dr. Nikitin?

http://www.vet.cornell.edu/BioSci/faculty/Nikitin/

 

Do you want to learn more about Shmoos?

http://deniskitchen.com/Merchant2/merchant.mv?Screen=CTGY&Category_Code=bios.shmoo

 

 

 



LINDA'S 68th (and my 150th)

Pretty surely a birthday

 Maybe her 60th, or my 72nd

 Marion (Linda's mother), Linda, me

 I still wear that shirt and ring, but not all that hair

 

Tomorrow is Linda’s 68^th birthday.  I greatly wish that I could have gone to 4^th Corner Quilts and bought her some fabric.  But as I’ve said someplace before, fabric is free in heaven, so I donated a bit to her Fred Hutch “Tribute” page instead.  If you would like to do likewise (and you certainly don’t have to, of course), go to http://getinvolved.fhcrc.org/site/TR?pg=fund&fr_id=1050&pxfid=2861 .  Don’t forget to specify “ovarian”.

Now that my ever so subtle attempt to extort more money from you is complete, I can get to further business.  Not only am I celebrating Linda’s birthday (tomorrow), but I  am also marking my 150^th blog!  The first 100 were churned out, on average, one every 77 hours.  Now the pace has slowed – to one every 94 hours.  It’s not that my enthusiasm has weakened; it’s more that the stuff I am studying now is tougher to assimilate and report on adequately.  If I am easy on myself and merely parrot the original articles you will sigh, look at the picture, then go on with your lives.  So I struggle to actually understand the subject well enough to make it comprehensible.  It’s good beneficial, salutary mental exercise; about the only part of my slowly mortifying body not affected by age is my brain.  I hope.

So, as I mentioned a week or so ago, I am trying to help Dr. Rivkin with one of his projects, by writing “laymen’s” versions of certain topics.  I will fill this blog out by giving you a taste. 

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CAUSES OF CANCER

Cancer results from one or more genetic accidents.  As described earlier, cancer will only occur if the mechanism that controls cell division is not functioning properly.  This proper functioning can be disrupted if one or more genes are damaged (mutated), or the factors that control which genes are expressed  (used to create functional molecules called “proteins”) are themselves disabled.  These changes can result from the effects of carcinogens (tobacco smoke, radiation, some chemicals, etc.) or can arise spontaneously because of random errors made during the process of cell division  Under some circumstances these genetic defects may accumulate, and may result in the loss of control over cell division and cell death.  If this occurs, cells will rapidly divide and multiply, resulting in a tumor. 

 Some people are particularly susceptible to cancer, probably because they are born with one or more important genetic defects.  For instance, women born with a mutation of a gene called BRCA are much more likely to develop ovarian or breast cancer than women without this defect.  BRCA is a tumor suppressor gene.  It  “codes for” a protein that acts to repair damage to DNA.  If the BRCA protein is unavailable to do its work, mutations may accumulate, and cancer may occur.  Other such genes are known that, when rendered non-functional, contribute to the likelihood of cancer, and probably many more remain to be identified.  It is important to realize that the presence of such genetic malfunctions does not lead inevitably to cancer; it merely increases the probability of developing cancer. 

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What Saul will do with stuff like this is unknown to me, but it does serve to keep me off the streets.  Otherwise I might be mugging teen-agers.

 



CANCER SCREENING. Specifically ovarian

No, she is not disguised as a unicorn, she is posing in front of an obelisk raised by the woman Pharaoh, Hatshepsut  

Karnak temple, 2008

 

It is only 2:30 and already this day has begun to qualify as the most boring, least productive, most  exceptionally tedious day of my life.  I am waiting, reluctantly, to answer the door when – and maybe if – the FedEx man arrives to deliver my new iPad.  He has tried twice and I haven’t been home.  If I don’t answer the door today the machine will go back to Apple, somewhere in the Cloud, and I will be doomed to many long telephone adventures – of the sort I hate very much.  Not only that: my stupid left knee has kept me from walking more than about 50 ft. at a time, precluding any useful activity outdoors.  If you think I am complaining too much over too little, you’re probably right, but I don’t care.  I am in a foul mood.

Well, one thing I can do is write a blog.  You may have seen this somewhere: it has been on the CBS and NBC evening news, Yahoo, and the NYTimes.  It appears that scientists at MD Anderson Cancer Center at the University of Texas have just released a announcement concerning the results of a clinical trial that have been conducting for ten years.  It seems that they have been measuring the level of the protein CA125 in the blood of healthy women yearly, then referring them to ultrasound if there is a marked increase. Medical science has known for years that CA125 is “up-regulated” in women with ovarian cancer.  The normal level of this blood marker in healthy (non-cancerous) women is 35 or less: I don’t know what the units are, and in my present state of mind I don’t care.  This has tempted the aforesaid medical science to use CA125 as an early warning signal, but this is discouraged by the authorities.  The problem is that things other than OVCA can affect CA125, and there is great variability between women.   

What the Texas group did was to monitor changes in CA125, and refer anyone with a marked jump for ultrasound.  They claim this has high “specificity”   This means that if you test negative, you probably are negative (don’t have OVCA).  They are rather more cagey about “sensitivity” – the probability that, if you have the disease, the test will catch it.  As with so many of these announcements we are cautioned that the test is not ready for prime time.

I don’t know what to think of this news.  In an important way, MD Andersen is poaching on the territory my group also occupies.  (Actually, of course, I don’t give a tinkers damn who develops a useful test, so long as one is developed.)  My Fred Hutch group also is using changes in CA125, together with changes in another protein called HD4, to select women for ultrasound.  We, however, are far more fancy.  We use something called a “parametric empirical Bayesian longitudinal algorithm” to select our “positives”.  If you are like me you know what each of those words (except perhaps "Bayesian”) means individually, but have no notion of what they mean all strung together.  Well, Bayes was a statistician who worked on conditional probability, I think it’s called.  He developed a method to re-compute probability in the light of accumulating evidence.  A childish example:  You have 10 M&Ms, and you are blind.  One is red, the others are black.  You are deathly allergic to red M&Ms, but you are very hungry.  Before you pick out one and eat it, the probability of getting the red one is 1/10, or 0.1.  Say you eat one and don’t die – but are still hungry.   If you dip into the bowl again, the probability of getting the deadly M&M now is 1/9, or 0.11.  If you still don’t die the revised probability of death by M&M is 1/8.  And so forth. 

So that, more or less, is the way that my groups plans to use repeat measurements of CA125 (and HD4).  It should work.  My greatest fear, though, is that it will reliably detect OVCA only after it is too late to do much about it.

The FedEx man has arrived!                                                                               

You can read the article yourself at http://news.yahoo.com/ovarian-cancer-screening-test-seems-promising-142618079.html 

 



GRACE: enjoy it

Linda's Team, May 28, 2013.  Photo Joe Mortimer

 

These are the hardy souls who stayed to sample my BarBQ

 

 

I am trying to wrap my brain around a new source of cancer information.  I was alerted to it by Dr. Rivkin, who seem likely to absorb much of my spare time  for many months  to come!  (I am emphatically not complaining.)  Anyway, the thing I am writing about is a web site called GRACE: Global Resource for Advancing Cancer Education.  You can get at it by directing your computer to www.cancerGRACE.org.  Unfortunately, it doesn’t cover ovarian cancer – yet.  I suspect that adding ovarian to GRACE  is what we are about. How I am going to help is beyond me, but I will try.  You should take the time to look at GRACE.  It will give you a renewed sense of how complicated cancer treatment is, and how hard society is trying to make it work.

 

The thrust of GRACE seems to be the providing of information to cancer patients.  I suspect, however, that it could do at least as much good if it somehow force-fed first line docs (”primary care physicians”) with news from the research world.  They are busy with sick people all day long, day after day;  it is thus perhaps understandable that they don’t read  all the medical journals on the shelf.  Heck, all I did was teach (and do a little research), and even so I found I had trouble finding time to read so much as the ABSTRACTS of the articles I should have read.  But I know that news of new cancer treatments diffuse slowly.  For instance, it was shown long ago that a drug – Proscar – reduces prostate cancer incidence by 25% - but it still is rarely prescribed. 

 

Anyway:  give GRACE a look.  It beats watching Mariners baseball.



ACRONYMS

Linda and Kristen.  Probably Christmas

 

 

From time to time I have complained about the ubiquitous tendency, almost a compulsion, on the part of  cancer researchers to festoon their papers with acronyms.  Several papers and/or proposals that I have attempted to understand had so many of these little capital-letter decorations that I have had to resort to compiling an Acronym Dictionary to make any progress.  Well, in my new role as a guy trying to help Dr. Saul Rivkin advance the cause of ovarian cancer independence in the human race, I have just been given a 90-page protocol to digest.  As evidence of Dr. Rivkin’s superiority to other researchers, or possibly simply of his compassion, the article begins with a Dictionary of Acronyms.  Three full pages of acronyms!  I foresee a long battle.       

The protocol describes a Stage 1 clinical trial that we (MRC) are running.  It is for women with advanced ovarian cancer who have relapsed.  Participants are being recruited from all over the west; at least one woman lives in Alaska.  I wish this trial had been available four years ago.



GOOGLE SCHOLAR IS A DISEASE

Linda's first trip to Lake City, Colorado

 

 

I don’t know who it was that turned me on to Google Scholar, but whoever it was has ruined my life.  Google Scholar is more addictive than crack cocaine, if perhaps not quite so harmful.  I have spent most of an afternoon playing with this digital toy, and now it is dinner time, the house is still a mess (and the cleaning lady comes tomorrow), and I haven’t defrosted anything.  Woe is me!

I started out investigating a crackpot notion that I could help Dr. Rivkin as he draws abreast of cancer research.  So, first I searched on “ovarian cancer”, anywhere in the article, years 2008 to 2013.  I got 160,000 hits, approximately!  (Ridiculous!  All the cancer researchers in all the world couldn’t read that many articles, not in five years, anyway.)  Then I asked for articles having “ovarian cancer” in their titles.  Same period.  I got 13,400 hits!  I gave up and made a list of the most-cited articles, on the forlorn hope that these were the best.  I know they aren’t: hell, my papers were never the most cited, but they were always the best.  But what more can one do? 

For comparison, I did a similar search, for articles with the word “paleomagnetism” in their titles.  Same period.  I got 342 hits.  I guess that comparison accurately reflects the importance of the two scholarly endeavors .  But what the heck; geologists have more fun.



TCGA. You'll have to read it to find out what that means.

The world's cutest picture

 

 

Linda’s sister Carolyn sent me a tip to a news article floated by Yahoo! about The Cancer Genome Atlas.  I wrote about TCGA earlier, but I can’t remember when.  (Maybe I should keep a running  log on what I’ve already written.  That way I can avoid making myself a liar.)  Anyway, Carolyn’s article dealt with the impact of TCGA on research, especially research into targeted therapies – fitting the drug to the specific problem(s).  I made a lazy attempt to run down the original article, but to little avail.  The clues I had at hand were that the article was about TCGA, published in Cancer Research, in 2013.  No author was mentioned.  I used Google Scholar to search on “The Cancer Genome Atlas”, “Cancer Research (journal)”, and “2013”.  Guess what?  Google Scholar furnished me with 126 papers meeting all those criteria!  One of them had already been cited 13 times – in eight months!  Heck, if I got 13 hits on one of my papers in a DECADE I would feel a success.  What is the answer?  Are there whole armies of cancer researchers, all writing papers and reading the literature most of the time?  If so, when do they do their actual work?  In geology, piling up multiple papers was legitimate, because – the content of our research being of vanishingly small actual importance – amusing ones colleagues with clever essays was a acceptable goal.  Cancer researchers, on the other hand, are supposed to spend most of their time and energy working on ways  to eliminate the damned thing – emerging  only rarely to report what they’ve found.   Ideally.

When you stop to think about it, dedicated cancer researchers are expending their energy trying to put themselves out of work.  Rather like dentists who campaign for fluoridation. 

As you can clearly see, I don’t really have much to write about today.  My main reason for doing so is to repeat the picture of Linda and Patches from the last blog.  For some reason Blogspot wouldn’t let me enlarge the picture at the end of the entry.  So here it is, full scale.

Here is the link

http://news.yahoo.com/largest-cancer-gene-database-made-public-232153763.html



EPIGENETIC APOCALYPSE NOW: I warned you.

This is going to be so boring that I will insert the picture LAST, and put you on your honor to read all the way to the bottom before you look at it.

Things you may already know:

                DNA consists of an enormously long sequence of four “bases”,  abbreviated A,C,T, & G.  These are types of organic molecules (nucleic acids) and are very similar, but with important differences.

                A sequence of three bases, called a “codon”, will “code for” an amino acid.  These things we call proteins are nothing more than long strings of amino acids, which naturally assume some characteristic shape.  The shape depends on the sequence and the chemical and electrical properties of the amino acids.
                Proteins are the workhorses of the body.  They can only do their jobs if they have the right shape.

                To make a protein from a DNA blueprint the sequence must first be “transcribed” onto a DNA-like molecule called a messenger RNA (mRNA).  Once transcribed the information is transported to a copying machine (ribosome) and “translated” into a chain of amino acids, which then folds and scrunches to make a protein.  Making a protein from a DNA sequence is called “expressing” it.

                All cells have the complete DNA sequence, but in specialized cell only a few are “expressed”.  You do not, for instance, grow hair in your teeth – although in your dissolute youth you may at times have thought you had.

Things you may not know:

                There are things called “promoters” that initiate “transcription” of a sequence of bases (a gene).  If the promoter is screwed up, the gene doesn’t get expressed properly, or at all.

                mRNA  frequently is modified after being transcribed by things called micro RNAs (miRNA),as well as by other proteins.  miRNAs are  a relatively new discovery, and I predict they will play a large role in cancer research.

                Sometimes the protein coming newly hatched from the ribosome also is modified before going to work.

I must say, the entire process strikes me as so blindingly and unnecessarily complicated that, in a way, it proves natural selection; natural selection by environmental conditions acting on completely random deviations..  It provides good  evidence against Intelligent Design;  if “designed”, the process   resembles a Rube Goldberg contraption slapped together  by a Designer with a peculiar sense of humor.

NOW, some things I think I know and partially understand that I would like to share with you:

                “Epigenetic” means “on top of, in addition to” – stuff like that” –genetics.  It is a science which treats of the ways that gene expression is regulated.  The reason that you do not grow hair in your teeth is because the genes for hair growth are blocked(in your teeth) by things called “epigenetic markers”. 

                An epigenetic marker can consist of something (a molecule) attached to the DNA strand.  Often this is a “methyl” group (one carbon atom attached to three hydrogens and carrying a positive charge.)  If a methyl group gloms onto the promoter for a gene (a specific length of DNA) it may stop that gene from being expressed.  Apparently patterns of methylation can be inherited, and after studying Nessa Carey’s book I even know how – but I know you don’t care, so I will spare you.  Another way that epigenetic markers modify gene expression is called “histone acetylation.”  This calls for more biology – but hang in there, I’m almost done.

Histones are proteins.  They form little knots (“octomers”, called “nucleosomes”) around which the DNA strand can be tightly wound.  Winding is essential; cells are so small you can’t see them, but a typical strand of DNA is six ft. long!  Clearly, to transcribe a stretch of DNA into RNA the knot has to be partially unwound.  The ability of a nucleosome to be unwound can be affected by a process called “acetylation”, which is the addition of an acetyl group to the histone proteins.  (For you would-be chemists and any other masochists, an acetyl group is CH₃CO-).  Apparently acetylation is not inherited.

There are many other kinds of epigenetic markers; Wikipedia will give you an entire paragraph-full of them.  But these are enough.

So why have I put you through all of this (you didn’t just skim, did you?)?  I did it because many novel cancer-fighting methods are based on epigenetics.  Say you have a gene that, when mutated, serves as an oncogene and stimulates cell division.  How to silence it?  Methylation!  Or, acetylate the hell out of the nearby nucleosomes, prevent  unwinding and thus transcription – ergo, no active oncogene.  They are hard at work on epigenetic drugs, and if they succeed they will deserve their BMWs, in my view.

I won’t do this to you again.  I promise.  Well, maybe once or twice more.  You know me; I never lie!

               

Linda and Patches, awake

If there is a cuter picture anywhere, I've yet to see it

MEA CULPA: but I have an excuse

 

 

In the Chilcotin, British Columbia

 

Cattle country.  Texas, with trees

 

Don’t give up on this blog!  I know, I know  ….. I haven’t written anything for several weeks, and you are tired of checking to find out if another little essay has appeared - mainly you are interested in the added attraction (the principal attraction?); a new picture.  I know that because my “hit counter” recorded only seven hits the past week, a new record low.   No, I am not lying in a gutter somewhere after celebrating the successful conclusion of Summerun North too enthusiastically.  Neither am I absorbed in my golf game, nor simply goofing off.  I am busy.  I am reading stuff (lots of stuff) at the behest of  Dr. Rivkin at the Marsha Rivkin Center, and writing a few things for my Fred Hutch group.  Also, I have had relatives, blood and in-law, as house guests for several weeks.  AND, I am writing my most blindingly boring and biologically challenged essay ever, on epigenetics.  Be warned, it is on its way!  But anyway, I want to reward your loyalty to this erstwhile barren site with another picture – and give you the good news.  Dr. Rivkin is full-time in pursuit of ovarian cancer.  I will help him in any way I can, or at least try to keep out of his way.  Ovarian cancer, your days are numbered!