READ THE ECONOMIST (dammit!)

Linda on the Oregon Coast, 2007
This is not the picture I wanted to show, but this is all the damned computer would allow me to show.
but it's a good picture nontheless
Carolyn, where are you when I need you?

Okay, so no more Mr. Nice Guy.  Heretofore I have suggested that you might want to read things – the NCI Cancer Bulletin, a New York Times article, something in the New Yorker or the Wall Street Journal, even the Stanford Alumni Magazine.  I have tried to be subtle, but persuasive, leading you to believe that you would actually ENJOY the article in question.  I’m glad I don’t know my success ratio.  So now,  no more persuasion.  GO IMMEDIATELY TO YOUR PUBLIC LIBRARY and read pp. 76-77 of the 9/8-14 Economist!  It contains an easily assimilated description of the ENCODE project – see my comment under ANOTHER SILVER BULLET TARNISHED, published on 9/6/12.

ENCODE may be one of the biggest breakthroughs in 21^st century medical research.  Moreover, the article is fun to read.  Well, you can wait a few days to go to the library, but remember – this will be on the test!

I just returned to Bellingham from a day-long conference, designed to elicit advice on our new series of research proposals from a panel of experts drawn from all over the country.  It was very interesting and, encouragingly, I understood quite a bit of what was said.  I will write about it later, as soon as my brain heals.  I probably shouldn’t relate this, but during a break I made a back-of-the-envelope estimate of salary monies spent on this day-long meeting.  It roughly $(n X 10³), where n has a range from 2 to 3.  I am confident that we got our money’s worth.

"OUTLIERS" Are they telling us something?

Linda waits patiently for me outside the British Museum

You know what an outlier is.  It's a piece of data that just doesn't fit.  It's a hockey player with all his teeth.  It's a short, swarthy, jovial Norwegian.  It's a McCain sticker on a Prius.  It's something that makes you look  again, and say "Huh"?

Back many years ago when I was doing real research I encountered lots of outliers.  Everybody in my field – most fields, I suspect – encounter their outliers.  Most outliers are nothing more than experimental error. Examples abound.  For instance, consider paleomagnetism.  A paleomagnetic outlier might be a direction that seems wrong; it doesn't match the rest of the measurements.  It might represent lots of things, all errors:  the rock you sampled had rolled down the hill  and you didn't know it; you wrote the wrong orientation numbers in the book; you read the wrong end of the compass needle; you recorded the wrong time of day; you gave it to the wrong graduate student to measure – etc., etc., etc.  I once wrote a paper describing a way to objectively identify a true outlier.  The purpose was to scrupulously avoid the temptation to retain – or pitch – an outlier depending on its influence on whatever you are trying to prove or disprove.    My simple little paper got trashed by two statisticians, with ill-concealed disdain.  I still think I’m right, but I’m afraid to say so in print.

The thing is, we all recognize that the outlier might not merely represent a mistake.  It might be trying to tell us something.

Well, an outlier spoke to researchers at Memorial Sloan-Kettering Cancer Center.  They investigated a drug called everolimus for its effect on advanced bladder cancer.  They concluded – using the conventional  blindingly confusing statistics – that it was a failure.  Into the dumpster with you, everolimus!

Fortunately, they noticed that one woman – out of 45 – showed a remarkable improvement.  In fact, she has now been in remission for 2.5 years and is going strong.  So they sequenced the genes of her tumor cells, and found “inactivating mutations” in two genes – TSC1 and NF2, if you are curious.  Then they tested other people with advanced bladder cancer and found that those with TSC1 mutations fared better than those without.  None of these other patients had the mutated NF2 gene. 

So, I wonder – what is this trying to tell us?  It clearly tells us to keep a little everolimus on the shelf, for that unfortunately rare case where a bladder cancer patient has the two mutated genes.  (They are doing further testing, of course.)  To my simple way of thinking, it also tells us that they should study just what in heck those two genes do.  Basic biology, guys. 

  

I got this from the 9/4/12 edition of the National Cancer Bulletin.

FLAVORED CIGARS?

In Canada, 1993

Only $99 Canadian.  We'd have bought it but it would have terrified our cats.

I’ve finally gotten around to reading the latest issue of the NCI Cancer Bulletin, only a few days before the next one comes out.  It is chock full of goodies about using the genome for various assaults on cancer, but they all require concentration and I feel lazy, as well as distracted by all the sunshine I see out the window.  So I’m going to write about a topic I could address in my sleep – smoking.

Starting at age 19, I smoked like a fiend, until age 30.  Quitting was the hardest thing I ever did, after watching Linda die, of course.  I started at Caltech, largely because the guy next door in my dorm gave away free samples.  For some people, I hear, tobacco smoking is not totally addictive – they can take it or leave it.  I can hardly believe that, because for me it was an all-consuming obsession.  I tried to quit many times, and after my final successful attempt I had a recurring dream: I was standing somewhere, with a cigarette in my hand.  A voice in my head said, “But, you don’t smoke”, and then another voice – clearly related to the Devil, replied “Oh, just one won’t hurt.”  I had some version of that dream for 30 years.  Don’t tell me it’s not addictive.

So, anyway:  It appears that American society is making progress against the scourge of underage smoking.  In 2000 the incidence of cigarette use among Middle School students was 10.7”; among High School students  it was 27.9%.  The same statistics for 2011 was 4.3% and 15.8%, respectively.  Good.

However, the same NCI publication has an article about – would you believe it? – flavored cigars.  It appears that the smoking of these little jewels actually is increasing.  Flavored cigarettes were outlawed in 2009, but the law doesn’t apply to cigars.  Apparently cigar smoking is considered less dangerous than cigarette smoking, because you rarely inhale.  It takes a real man, with hair on his chest, to inhale a cigar.  It also helps to be stupid.  I know, because I’ve done it.  It seems that adding a flavoring ”masks the natural harshness and taste of tobacco.”  Oh, great.

An interesting sociological aside:  Flavored cigars are favored by women, as well as by poorer and less well educated people.  They are most popular in New Mexico and least popular in New Hampshire.  So, what does all that mean?



OVARIAN CANCER AWARNESS MONTH: Spread the word.

                        Linda at four.  Cute from the start.

Then she got cuter.



Suddenly I am neck-deep in important stuff to write about.  I haven’t even looked at the NCI Cancer Bulletin for September 4^th, except to note from the “cover page” that it has lots of articles on the genome and cancer.  I am dipping my toe into an incredibly important info-dump (code name ENCODE) detailing a vast, coordinated set of new genome studies.  (36 separate papers from three different journals, all published on the same day.  One of the PIs here at the Hutch told me not to attempt to read the original papers; just read the press releases instead.  He has concerns for my mental health.)  There also is an article in the NY Times about new developments in the battle against lung cancer, which has important implications for using targeted therapy  for  many other kinds of cancer.  Again, this is genome-based.  However, because this is National Ovarian Cancer Awareness Month (you didn’t know that, did you?) – and because ovarian cancer is the disease I hate most in all the world – I am going to alert you to another NY Times* blurb, this one titled “Ovarian Cancer Screenings Are Not Effective, Panel Says”.  You can read it for yourself by going to http://nyti.ms/S4Jkiy.  It is easy going.

The gist is this:  The United States Preventive Services Task Force (the same group so hated and reviled by  urologists for their recommendation against using PSA to test for prostate cancer – see blog entry for 3/27/12, as well as having been stoned and run out of town for suggesting that women should not have mammograms before the age of 50) now says something that everybody agrees with:  you should not use currently available screening techniques on healthy women to detect ovarian cancer.  Current methodology consists of testing for the abundance of the protein CA-125 measured from a blood sample, followed by ultrasound.  CA-125  is well established as being  associated with ovarian cancer.  The problem here is that CA-125 can elevate for any number of reasons, not merely those that are scary.  Furthermore, ultrasound detects ovarian enlargements of all sorts, not all lethal.  A vast study shows conclusively that there is no gain in longevity from such screenings.  Moreover, of those screened about 10% received false positives, leading to unnecessary surgery.  The article states that this screening technique leads to about 20 surgeries for every cancer detected.  Too much needless pain, and too much expense – although the USPSTF always goes to great lengths to assure you that they don’t take expense into consideration.  Still, about 1/3 of doctors will recommend this screening, or not talk you out of it if you ask for it.  So, be warned.

Note that this applies only to healthy women.  If you have a family history or you are carrying a BRCA mutation, or if you experience the symptoms below, for God’s sake get screened.

·           *   *   *   *   *   *   * 

Ovarian Cancer Symptom Index

                Any new and persistent incidences of:

Bloating

Pelvic/abdominal pain

Trouble eating, or feeling full quickly

Urinary symptoms such as urgency or frequency

·           *   *   *   *   *   *   * 

This article also contains the usual disgusting statistics about the prevalence – and mortality – of ovarian cancer.  The American Cancer Society estimates that 22,280 new cases will be diagnosed this year in the U.S., and 15,500 women will die.  Like I’ve said many times before, ovarian cancer is  crying out to be wiped from the face of the earth.

By the way:  the article ends with the words “We’ve got to find something else” (referring to an early-warning screening protocol.)  That’s exactly what my group at the Hutch is working on.

*My wide-ranging reporter Dick Ingwall is to be thanked for alerting me to these NY Times articles.  Thanks, Dick.  Since he pays for and reads it, I am spared the effort and expense.  The only problem with reading these bits on-line is that you are always welcomed by Michelle Obama, who will invite you to dinner at the White House.  “Air fare will be provided!”  Now, how DO they manage that?

ANOTHER SILVER BULLET TARNISHED **

 On our Mexico trip

She loved little kids of all sizes    

I would have liked to believe that, if only we knew all about a person’s genome, we could predict his or her lifetime cancer risk, thus enabling us to initiate prevention early enough to chop off  most  cancers at their roots.  Of course, I knew it wouldn’t be that simple – I am gradually realizing that nothing in this business is simple  - but I had hope.  A paper in Genomics, by N. J. Roberts and five others, published in May of this year, has dashed cold water on my youthful enthusiasm. 

These guys used registries* of identical twins (“monozygotic”, if you want to appear learned), and also dizygotic twins (we call them fraternal twins.)  Monozygotic twins have precisely the same genome at birth; dyzogitic twins don’t.  The bottom line in this research, as I get it, is this:  The relative “heritability” of a disease represents the frequency with which both identical twins get a given disease, as compared to the same frequency for fraternal twins.  For instance:  If every time an identical twin got a disease her sibling did too, but the same did not hold for  fraternal twins, then the disease is heritable.  (Actually, what we are talking about here is a propensity to develop the disease; things other than genotype obviously are involved.)  Then they did a lot of fancy mathematics, and came to the discouraging (but predictable?) conclusion that, for most diseases, sequencing genomes at birth would be of minimal value.  In the case of the disease most interesting to me – ovarian cancer – only about 12% of people with the disease would have tested positive using their whole-genome algorithm;  alternatively,  a positive (bad) test result indicates only that the patient is  about 10% more likely to develop the disease than the general population.  And so, another silver bullet is tarnished. 

This is not to say that genome sequencing is useless.    Far from it.  There are specific genes that, when mutated, confer a high probability of contracting a specific disease – the BRCA1/2 genes for ovarian and breast cancer, for instance.  The whole genome studies these guys did suggest that they might be useful  for Alzheimer’s disease, or male coronary disease, or even Type 1 diabetes, but hardly so- and prohibitively expensive - otherwise. 

*Mostly from the Scandinavian countries, which apparently accumulate vast storage bins filled with neatly ordered data.   Now we know what they do during those dark winter months, other than write mystery stories and create more Scandinavians.

** Ah, come on, guys!  Won't SOMEBODY read my blog of 9/1/12?  It is embarrassing to see the big goose egg in the column headed "page views".  You don't need to read it, just bring it up so the zero will disappear.

Thanks.

ANOTHER RANT, MAYBE ONE TOO MANY.

 

Linda with what may be a chestnut sprout

Probably Michigan

I have just finished reading a review article on the cancer stem cell (CSC) hypothesis, by Diehn et al, published as an Open Access Article by the NIH, in 2009.  I really believe that I got the overall drift of the subject, even though I draw a complete eye-blurring  blank on some of the techniques discussed.  I can’t say that I came away from the paper with joy and anticipation in my heart.  The “magic bullet” CSC is not.  I will not attempt to tell you anything much about what I have learned, partly because I might get it wrong, but mainly because it would bore you to death.  Instead, I report the following:

In geology we have something called the Geological Names Committee.  If you have mapped a stratigraphic unit, or a fault, or a batholith, before you can name it you are required to submit your name to this committee.  They will check to see if there is something else already called by that name, and that your name conforms to a fairly detailed set of naming rules, a set that has been in place since not long after Darwin.  This can be annoying, but it certainly saves the reader  a lot of head-scratching.  Now, as far as I can tell, there are no damned rules that govern the naming of things in biochemical-medical research.  They often name things with a few capital letters, such as BRCA.  They all know that stands for a gene and comes from Breast Cancer – but, of course, outsiders are mystified, at first.  (It took me a month to figure it out).  Also, I think, they use the same letters to refer go a gene AND the protein it codes for.  Why not use BRCA for the gene and brca for the corresponding protein.  Is that too much work?   And then there are funny little objects called things like Hedgehog, Dumbkopf, Hunchback, etc.  Biochemical humor, I guess.  There are of the order of 10⁵ genes and a comparable (or larger) number of other important things.  Wouldn’t it be efficient to use some system in naming them?  Come on , guys, have mercy on us.  Think of us as Dumbkopfs.

There are a heck of a lot of people working on cancer research. I used Google Scholar to find the Diehn article.  Google Scholar informed me that my search (cancer stem cell hypothesis) yielded 26,863 articles – and that’s just since 2009!  Has anybody read ‘em all?  I sincerely hope not.

More evidence:  The same review article, 4.3 pages long, cites 66 other related pubs.  If cancer researchers really read all this stuff,  either they don’t do much  actual research themselves, or they have one heck of an impoverished  home life. 

I am starting back to work at Fred Hutch next week (although if I keep on writing things like this they may fire me)!  My ribs are reasonably healed and I have learned to cope with my heart monitor.  Got lots of work to do before I win that Nobel.

OBESITY, CANCER & OTHER DEPRESSING TOPICS

Linda and an unidentified Stalcup grand child.

If there was a baby anywhere in the room, Linda would be next to it.

This was at the Bebee family reunion in Big Bear

So, it is a warm, sunny Saturday, the 1^st of September.  I just got through lunch (Blueberry Boy-Bait*  and ice cream).  I had intended to get on my exercise bike, but instead decided that my broken ribs still provided a viable excuse to do nothing instead.  I am going over to my friend Phil’s house later this afternoon for a beer, but I had time to kill.  This being the case, I plopped my weary bones down on an easy chair and picked up Quest, which is the quarterly magazine of the Fred Hutchinson Cancer Research Center.  Earlier this morning I had weighed myself, then – on a lark – calculated my body-mass index.   I was within 1.7 points of “obese”.
 

The first 13 pages of Quest concerned how obesity, bad diet and a sedentary life style promote cancer and other forms of life-threatening health problems.  Bummer!
 

The American Institute for Cancer Research estimates that obesity is implicated in about 14% of all cancer deaths.  Women with a body-mass index of 40 or more (this is really obese) have cancer death rates 62% higher than similar, thinner women.  Obese men don’t come off well, either – their excess death rate is 52%.  One researcher in this field was quoted as saying that obesity is almost like the new smoking.  That’s certainly not good: people have to eat but they don’t have to smoke.  (Quiting can be damned hard, though – just ask me.)

So just why is obesity so bad?  Here are a few things I abstracted from these depressing few pages.

First, it turns out that fat cells actually secrete hormones, in particular estrogen, testosterone, and insulin.  Estrogen is well established as an accelerator of cancer development.  Too much insulin seems to function similarly.  Testosterone in obese men is converted to estrogen (surprise!) and has all kinds of deleterious effects, none specifically spelled out.

Second, for some reason too much fat leads to a state of constant low-grade inflammation, which can’t be good for you, although what it does and why it does it is not explained.  

Fred Hutch has a number of experiments going on in which people are fed precisely measured diets and/or subjected to precisely monitored exercise regimens.  Apparently diet and exercise are cancer-preventers in their own right, above and beyond their obvious role as weight-reducers. I get the impression that volunteers are fed free food, which would be a real plus.  Apparently Mexican food is better for you than Norte Americano food, which seems strange.  Maybe it's the margaritas that go along with it.

And so, on and on.  Everything I like to eat seems to be anathema: cancerous, fattening, or both (not to mention what it does to my heart.)  I drink way too much.  I don’t get enough exercise.  I sit around reading, or typing on this infernal lap-top (which has eaten parts of this essay twice in the last 10 minutes!),  way, way too much.   The peak of my exercise intensity involves nine holes of golf, on a short course.    So, should I change my ways and live to be 90, or should I ignore all this good advice proffered by Quest and live to be 88?  I’m not really asking – I know what I’m going to do.

By the way, you can get most of this information off the Fred Hutch web-site.  If you give them a donation, they’ll probably send you paper copies for the rest of your life.

*Believe it or not, there is such a thing - and it's delicious.  Google for the recipe.