EPIGENETICS: ONE MORE THING I REALLY DON'T UNDERSTAND

Linda and our friends John and Joan McManus

Catalina Island

Last November I wrote a blog called “Grandma’s Curse”.  The gist of that little essay was that cancer researchers had discovered that “epigenetic” factors appeared to conspire somehow to allow mice to inherit bodily changes inflicted on their grand-parent mice – in complete contradiction to Francis Crick’s “Central Dogma”, which states that characteristics acquired by a person (or mouse) during its lifetime cannot flow back into the genome and become heritable.  In other words, according to Crick,  Lamarck was completely wrong about how evolution occurs, and Darwin was completely right.  I said at the time that I didn’t understand “epigenesis”.  I still don’t.

Now, however, epigenesis is getting to be a hot topic.  For example, there is an article in the magazine “The Week” entitled “The ‘switches’ on your genes", and subtitled “New research suggests that people’s experiences, not just their genes, can effect the biological legacy of their offspring.”  In other words, Lamarck was right – at least partially.  The same article defines “epigenetic” as “on top of genetics”, and goes on to say that it concerns the molecular “switches” that tell the various genes when to be “expressed “ – that is, when to do their job by making proteins.  I gather from this article that life experiences, environment, etc., can affect these “switches” – and somehow the altered switches themselves can be inherited.  Really:  I don’t get it, and I would sleep better at night if somebody would enlighten me.  In a nutshell, here is what I don’t understand”

What in heck are these “switches”, anyway?  Are they proteins?  They must be some kind of organic molecule, that’s for sure.  If they can be inherited, doesn’t it follow that they somehow are coded for in the DNA?  If they can be altered by environmental factors and/or life experiences – and inherited – then, it would seem, our experiences can alter our DNA.  Was Lamarck right after all?

I should have stuck with plate tectonics.

   

OF MELANOMA, TELOMERASE, AND WINDSTORMS

Linda at Oxford

It is hard to just sit down and write when you don’t feel like it.  I have something important to write about, but I can’t summon so much as a drop of either inspiration or enthusiasm.  The problem probably stems from the weather; it is cool and sunny today, and something inside me keeps saying: “Get your butt outside and get some exercise!”  And I would, but it also is blowing hard.  If I could drive to a deep wash somewhere and walk I probably would be sheltered – but it has been raining lately, and I don’t trust a sandy wash after a rain.  So, weather wimp that I seem to have become, I will stay inside and write another blog.

Dick Ingwall again has alerted me to an important article in the NYTimes.  It appears that two research teams have simultaneously reported on an investigation of the genomes of certain cancer patients, specificially those with melanoma.  They sequenced the so-called “dark matter” of DNA, which is a cute reference to the roughly 98% of DNA which does NOT code  for a protein (are not “genes”, sensu strictu.)  They found a mutation of a particular sequence that codes for a regulartory molecule: something that tells a gene when to turn on and when to turn off.  In 70% of the 70 melanomas studied, the same short region of “dark matter” was mutated.  Interestingly, the identical mutation was found in examples of liver and bladder cancer.  A separate study also published found that some people for whom melanoma “runs in the family” (poor devils) INHERITED this mutation.  So, this little DNA mistake is a nasty brute, worthy of further study.

If I get this right, the mutation is responsible for the proliferation of telomerase in the tumor cells.  You remember telomeres and telomerase from previous blogs.  Telomeres are the protective stuff at the end of chromosomes that prevents premature cell death.  Telomerase is an enzyme that rebuilds the telomere string – in stem cells and, regrettably, cancer cells as well.  If the cancer cells didn’t have telomerase handy they would die normally after a few divisions, not spread without limit, to the detriment of the organism.  So far it has not proven possible to attack cancer by going after its telomerase.  However, efforts are underway – and progress is being made, I certainly hope.

This is an interesting article to which I have not done the least justice.  You can read it yourself at: http://nyti.ms/WpggGy.  .  It also is possible to read the abstracts of the two scientific papers referred to in the Times story, by using Google Scholar.  You can even get the articles themselves; for $20 per, but - unless you majored in biochemistry - don't bother.

I am going to go back through this blog and find all the times telomeres have come up.  I will report, in a Comment.  I think we’re on to something.

MORE REASON TO READ THE ECONOMIST

Hiking in Scotland, 1999

There are back-to-back interesting medical articles in the most recent Economist.  (Well, maybe not the most recent.  The magazine is forwarded down here from Bellingham, and I forget to pick up my mail for three or four days sometimes.  Anyway, it’s the January 18^th edition.)

The first article reports that the “longevity gap” between men and women is narrowing, at least in developed countries.  For instance, the life expectancy of women in England and Wales born in 1967 was 6.7 years greater than that of comparable men.  Now the gap is less than three years. 

Some of the causes are obvious.  In former times men smoked much more than women, and died as a result.  Now, men are smoking less.  So are women, but at a lesser rate than men.  This is an important driver.  Another important driver is alcohol use – not all of us can have white wine for breakfast, champaign with every dinner, Scotch in between,  live to be 90 AND retain your marbles.  That would be Winston Churchill; the rest of us are human.  Formerly women drank tap water and implored their husbands to do the same.  Now they slam back the good stuff regularly.

However, there are good reasons to believe that men will never catch up.  For instance, if you are female you are XX (chromosomes), if male, XY.  The Y chromosome is a dimunitive little runt that carries few functional genes.  Thus, for traits coded for by genes on the X chromosome, males have only one shot at getting it right.  That is why, for instance, that  hemophilia is mostly found in men.  Another dirty trick nature has played on men is to give them shorter telomeres than the ladies.  Why this should be seems to be a mystery, but it is true.  That means that cells in men shrivel up and die sooner than comparable cells in women. 

And, of course, testosterone.  An excess of this hormone gets us males into trouble in all sorts of ways.  This accounts for he fact that death rates between men and women are most different in their 20s, when males are busy advertising their evolutionary fitness by doing all sorts of things that are stupid, dangerous, ill-advised and, usually, counter-productive.

The second article is equally interesting, but I’ve spent so much time on the first that I will just tell you what it is about.  It is about the researchers that have succeeded in converting normal specialized stem cells into “pluripotent” stem cells, of the type we are reluctant to “harvest” from embryos.  The method was discovered by two groups in 2007, and now is beginning to be utilized by some of the bigger drug companies.  The potential benefits – and profits, of course – are enormous.  A picture shows one of the scientists involved in this transformation smiling at something in a test tube.  The caption is “I will now turn these cells into gold.”      

EARLY WARNING SIGNALS: More progress.

Shopping and sightseeing

Vancouver, 2009

I have never claimed to be a hotshot mathematician.  I always WANTED to be a hotshot mathematician, but no matter how hard I tried, I just wasn’t one.  It always seemed like there was something macho about proving your point with mathematics; sometimes, I suspect, I almost would rather have been wrong – but have used flashy math - than to get it right.  (No, not really, but almost.)  Mostly I just used trig and calculus, and of course the arcane math of paleomagnetism that only another paleomagnetist would care a fig about.   One topic I managed to keep at arm’s length for 50 years was – statistics.  So now, here I am:  running into statistical arguments in most of the papers I read, and not knowing what in hell they are talking about.   So, I am uniquely unqualified to write the remainder of this blog – but here it comes, anyway.  The topic: early detection of ovarian cancer.
 

As you know, my group at the Hutch is focused on the early detection of ovarian cancer, mainly using “markers” that can be measured from a blood sample.  One of these markers will be familiar to most of you – CA 125.  It turns out that CA 125 is another name for the protein mucin 16.  (The name CA 125 came about because MUC16 was the 125^th cancer antigen used in a study of a particular ovarian cancer cell line.  Back in 1981.)
 

The title of “our” paper almost says it all: “Longitudinal Screening Algorithm That Incorporates Changes Over Time in CA 125 Levels Identifies Cancer Earlier Than a Single-Threshold Rule”  It appeared in the Journal of Clinical Oncology just last month.  It reports the results of a “retrospective” study of women who had been involved in the PLCO  (Prostate, lung, colorectal and ovarian) Cancer Screening Trial.  This was a massive effort involving nearly 80,000 women aged 55 to 79, who were followed for many years.  “Retrospective” means that the medical histories of these women were known: the research then consisted of using – you guessed it - statistics to determine what test or tests would have done the best job of detecting their tumors early.  By “single-threshold rule” is meant a fixed concentration of CA 125, above which further tests are recommended.  The “normal” range for CA125 is 0 to 35, so an example of a single threshold rule would be to recommend ultrasound for any woman who had a concentration >35.

  There is a big problem with this, if applied to the general population; there are lots of thing other than ovarian cancer that can raise the CA125 level, and among  healthy women the CA125 level can vary significantly.  Such a test is so low in “sensitivity” and “specificity” that the NIH, or some equally august body – I forget which – has recommended against single-threshold screening for the general population, although the method is useful in the high-risk population. ( I believe that my group at the Rivkin Center is engaged in just this sort of screening.)  

So, naturally, any screen that can be tailored to the individual woman should be a big improvement – and that is precisely what my Hutch group is proposing.  The tool of interest is called a “parametric empirical Baysian longitudinal algorithm.”  What follows (in the paper) is a mind-glazing bit of mathematical explication, which I fail to follow.  Fail miserably, in fact.  (I will show the equations to my statistical drinking buddy Jay Teachman when I get home; maybe he can enlighten me.)  Anyway, the PEB algorithm worked significantly better than the single-threshold test.  It detected more tumors, earlier – ten months earlier on average, and at a lower CA 125 level.  Ten months isn’t much, but it could give the oncologist a head start..  What is needed, of course, is a test that spots a cancer case at the moment it first protrudes its ugly little head.  And then, a way to kill it. 
  

There seems to be a competing method called ROCA, which codes for Risk of Ovarian Cancer algorithm.  I gather that it, too, is more sensitive than the single threshold method, but diligent Googling so far has failed to reveal to me how it works*.  Maybe somebody can enlighten me.
 

And so, yeah, this was a dull blog, and overlong to boot.  I needed an excuse to post another picture.  The weather here today  was mid-70s, sunny, light breeze.  How was it where you are?

*However, see my Comment, below

DEFINITELY NOT OC: In praise of ME!

It is past time to toot my own horn.  As of today I have written exactly 100 blog entries, in 322 days, giving me an average rate of one blog every 77 hours or so.  According to Google my blog has been viewed 5276 times, by people in 17  countries.  I have “readers” in such unlikely spots as Latvia, Cambodia, and Thailand.  People in Poland and Russia seem to be particularly fascinated by my blog  (Actually, as I spelled out earlier – I think some of the latter hits are from machines, not human beings.)  Nearly all of these 100 blogs have something to do with cancer research, and/or my adventures in biochemical wonderland.  So, to celebrate, I post a picture of ME!

The picture was taken in December of 1951.  I had just finished my first quarter at Caltech.  The car - my first - was a Hudson Terraplane business coup.  It was heavier than a tank, and consumed nearly as much gasoline (but, at 25 cents the gallon, one could live with that.)  Notice the shoes.  My mother did most of my shopping in those days, and she tried to keep me up with the fashions.  They were swade, if I remember correctly.  Notice the rolled up jeans.  That was studly in those days.  When you were smoking, and I was just beginning to smoke, you were supposed to flick your ashes into the upturned cuffs.  The house in the background is 665 Palm Ave., Beaumont, California, where I grew up.  It is still there, but looks seedy.  The palm trees are enormous now.

I had meant to write something about a paper my group at the Hutch just published, but it is full of statistics I don’t understand so I need to give it another go.  And, don’t worry, from now on the pictures will feature Linda.

ANOTHER GLIMMER OF HOPE?

In Norway, 2007

and about to descend the "Trollsteigen", the most incredible highway on earth

Friday, January 11, 2013 2:14 PM

I am rolling in wealth, help-wise.  As I have said many times before, I couldn’t do this blog without the assistance of my indefatigable research assistant, Dick Ingwall.  Now it appears that Dick will have help.  I am going to report on a story about new uses for the Pap smear that have promising implications for ovarian cancer early detection.  It appeared in the New York Times, as reported by my granddaughter Olivia Kelly from her classroom at Western Washington University, as well as by  Dick from his sickbed in Borrego Springs, CA.  My daughter Kristen spotted it on American TV (I missed it: I was involved in a Best of Gilligan’s Island marathon.)  Finally, “parkfriend” ran on it on Canadian TV from her living room in Toronto.  As I said, my cup runneth over.  Keep up the work, gang, and I will have plenty to write about.

So, it appears that some people from Johns Hopkins University in Baltimore have found reason to believe that a side-benefit of the Pap smear eventually may be the early detection of ovarian and endometrial cancer -  given much more study and not a little luck.  Many (most?) women get regular Pap tests, which are very effective at detecting the presence of cervical cancer, often at an early, highly curable stage.  The Hopkins team reasoned that a few cells from other types of uterine cancer also may be present in the Pap smears of women with endometrial or ovarian disease.  However, if so they would be there in such minute amounts as to be undetectable by ordinary methods.  Fortunately, it turns out that, the genomes of many types of endometrial and ovarian cancer have been sequenced and  a list of cancer-associated mutations compiled.  Using methods not described (but probably involving some very expensive machinery), it appears to be possible to spot cells with these mutations.  This can be done with only marginally little clinical fuss, and-  maybe, eventually - at no great expense.  Thus, hooray!

But take another look.  The original research involved woman already KNOWN to have either endometrial or ovarian cancer.  The test, in its early stages, detected 100%of the endometrial tumors, but only 41% of the ovarian tumors.  Moreover, a concurrent  experiment to determine if the test turned up false positives (it didn’t) involved only 14 women.  One can foresee some vast clinical trials in the immediate future.  As one scientist quoted said, “It’s not ready for prime time”.

But, anyway, take a little hope.  We’ll lick this damned thing yet.

P.S.  Want to read the NYTimes article?: http://nyti.ms/VThUQp

The CBC news release uses fewer obscure words:  http://www.cbc.ca/news/health/story/2013/01/10/ovarian-cancer-pap.html.  , and moreover has a very good explanatory diagram.

THE KIND IF SCIENCE I REALLY LIKE. But what do I know?

Linda and her Mom, southern Michigan, 2001

She loved dry leaves, fall, and her family.

It has been over a week since I posted anything to this site and I know that most of you are worried and distressed, so I will tell you what is going on.  Then, I will slip in some thoughts on cancer research, and end by introducing you to somebody I wish I knew – Dr. Titia de Lange.

First, about me:  I have been in Borrego Springs since December 28^th; that is, for a little bit more than a week.  I have been out to dinner three times, worked daily on some stuff I am doing for the Marsha Rivkin Center for Ovarian Cancer Research, explored the desert three times with my new jeep (a joy!), and gone out with the Paleo Society on one field trip.  The latter experience was less than wonderful.  I was so lacking in energy (and also in pain pills) that I had to quit early, after only a few hours.  I am afraid that the Paleo people are worried about me, to the extent that they surreptitiously assign one of the members to follow me and make sure I don’t collapse and die in some remote dry gulch, to be found by future Paleo people many  decades hence and confidently identified as a tiny ground sloth.  At any rate, on this last trip there was one guy who never let me out of his sight.  Also, the leader kept radioing me to find out where I was.  It may be that my efforts are a net loss to paleontology but I don’t care; if I get back in shape it will be fun again.

Now some thought:.  If you are a faithful reader of these things you will know that from time to time I grumble about the empirical nature of the research I run across, which I characterize  (somewhat unfairly, I suspect) as “Who gives a damn WHY it work; if it does, run with it.” I fully appreciate that point of view.  However, I continue to suspect that the ultimate eradication of most,  perhaps all, cancers will require a very thorough understanding of their basic biology.  That’s why I was happy to read about the career of Dr. Titia de Lange.  She works on telomeres, and has done so for many years.

Why is it that, in NIH, NCI, Fred Hutch, etc., publications that contain pictures, the women scientists never look like they are more than 40 years old, whereas the men appear to be contemporaries of Darwin?  Anyway, Dr de Lange appears to be no older than our (WWU Geology) youngest women faculty, although she got her Ph.D. in 1981.  She is determined to ferret out the secrets of telomeres, by studying their basic biology.

You remember telomeres.  I wrote about them on July 12, 2012.  That blog bit stirred up a little excitement, in the form of a real live Dr., who wrote in to set me straight.  Anyway, telomeres are short, repeated, “non-coding” sequences of nucleotides found on the end of chromosomes.  Their purpose in somatic cells (all cells except germ – sex – cells) is to protect the chromosomes from damage during replication (that is, to keep them from losing their tails when the cell divides).  It seems that a bit of the end of these things is lost with every cell division.  In the cell’s youth the part lost is the otherwise-useless telomere.  When the telomeres are all used up the chromosome experiences real damage, and then the cell happily dies.  In germ cells (and other stem cell?) the telomeres are NOT used up, because of the good offices of an enzyme called telomerase.  Telomerase rebuilds the telomere chain as fast as it is used up, hence these stem cells don’t go into oblivion.  In a sense, they are immportal.  (Hence the name of the Henrietta Lacks book.)

But, it appears that cancer cells ALSO have telomerase.  Thus, they don’t curl up and die after a few divisions, but instead just keep multiplying.  Why in heck is telomerase found in a set of cells that ideally ought to croak?  How can evolution account for THAT?  Damned if I know.  (Joanne, if you know but can’t get the Comment machine to work, Dick will be happy to help.)  Anyway, this is the sort of problem that Dr. de Lange is devoting her life to solving.  When she answers that question  a broadly applicable therapy for cancer may be just around the corner.  Go, Dr. de Lange - you are my hero!